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| Gene Symbol | MLH1 | ||||||||||
| Synonyms | COCA2 | FCC2 | hMLH1 | HNPCC | HNPCC2 | LYNCH2 | MLH-1 | MMRCS1 | ||||||||||
| Gene Description | MLH1, mutL homolog 1, is a tumor suppressor (PMID: 30562755) that dimerizes with Pms2 to form a component of the DNA mismatch repair (MMR) system (PMID: 16873062), and is associated with microsatellite instability (MSI) (PMID: 30121009) and genomic stability (PMID: 31747945). MLH1 promoter hypermethylation, resulting in Mlh1 deficiency, is frequently associated with sporadic colorectal, gastric, and esophageal cancers (PMID: 23555617, PMID: 21988782, PMID: 28224663, PMID: 28454461), and germline MLH1 mutations are associated with Lynch (Hereditary Nonpolyposis Colorectal Cancer) syndrome (PMID: 15528792). | ||||||||||
| ACMG Incidental List v3.0: |
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| Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|
| A111P | missense | loss of function | MLH1 A111P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A111P confers a loss of function on Mlh1, as indicated by reduced expression of Pms2 and Mlh1 in culture (PMID: 36054288) and a loss of mismatch repair activity (MMR) in in vitro assays (PMID: 20020535, PMID: 17510385) and in cell culture (PMID: 31784484, PMID: 36054288). | |
| A111V | missense | loss of function | MLH1 A111V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A111V results in loss of mismatch repair (MMR) activity compared to wild-type Mlh1 in yeast assays and decreased MMR activity in an in vitro assay (PMID: 17510385). | |
| A120S | missense | unknown | MLH1 A120S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A120S has been identified in sequencing studies (PMID: 24755471), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| A128P | missense | loss of function | MLH1 A128P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A128P confers a loss of function on Mlh1 as indicated by decreased mismatch repair (MMR) activity in in vitro assays (PMID: 17510385, PMID: 17135187), loss of Pms2 interaction in an in vitro assay (PMID: 17135187), loss of interaction with Pms2 and Exo1 in yeast two-hybrid assays and failure to bind LexA in a reporter assay (PMID: 12810663). | |
| A160V | missense | no effect - predicted | MLH1 A160V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A160V results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385) and retains methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| A20V | missense | unknown | MLH1 A20V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A20V has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| A210T | missense | unknown | MLH1 A210T lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A210T has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| A21E | missense | unknown | MLH1 A21E lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A21E results in protein expression comparable to wild-type in culture and interaction with Pms2 similar to wild-type in a yeast-two-hybrid assay (PMID: 21404117), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| A21V | missense | loss of function - predicted | MLH1 A21V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A21V results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| A281V | missense | no effect - predicted | MLH1 A281V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A281V results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| A29S | missense | no effect | MLH1 A29S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A29S does not alter the expression of Mlh1, has mismatch repair activity comparable to wild-type Mlh1, localizes with Pms2, and is predicted to be non-pathogenic (PMID: 16083711, PMID: 21120944). | |
| A31C | missense | loss of function - predicted | MLH1 A31C lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A31C demonstrates reduced mismatch repair activity (MMR) relative to wild-type Mlh1 in an in vitro assay (PMID: 20020535), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| A410T | missense | unknown | MLH1 A410T lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). A410T has been identified in sequencing studies (PMID: 26401016), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| A42V | missense | unknown | MLH1 A42V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). The functional effect of A42V is conflicting as it results in decreased mismatch repair (MMR) activity in a yeast assay (PMID: 15475387), reduced Pms2 and Mlh1 expression and altered splicing, but leads to normal MMR activity in culture (PMID: 36054288). | |
| A441T | missense | no effect - predicted | MLH1 A441T lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). A441T results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| A492T | missense | loss of function - predicted | MLH1 A492T lies within the EXO1-interacting region and C-terminal dimerization domain of the MLH1 protein (PMID: 22753075). A492T results in repression activity similar to wild-type Mlh1 in a yeast reporter assay and interaction with Pms2 similar to wild-type Mlh1 in a yeast two-hybrid assay, but results in decreased Exo1 interaction in a yeast two-hybrid assay, decreased Pms2 binding in an in vitro assay (PMID: 12810663), and decreased MMR activity in an in vitro assay (PMID: 17510385), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| A539D | missense | loss of function - predicted | MLH1 A539D lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). A539D demonstrates no splicing defects (PMID: 18561205) but results in reduced methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| A541Dfs*50 | frameshift | loss of function - predicted | MLH1 A541Dfs*50 indicates a shift in the reading frame starting at amino acid 541 and terminating 50 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). A541Dfs*50 results in loss of interaction with Pms2 and Exo1 in a yeast-two-hybrid assay, reduced Pms2 expression in an in vitro assay (PMID: 12810663), and due to loss of the C-terminal domain (PMID: 16338176), is predicted to lead to a loss of Mlh1 protein function. | |
| A586D | missense | loss of function - predicted | MLH1 A586D lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). A586D results in reduced methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| A586P | missense | loss of function | MLH1 A586P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). A586P results in decreased protein expression of Mlh1 (PMID: 23403630, PMID: 20533529) and Pms2 in culture (PMID: 20533529) and decreased mismatch repair activity in yeast assays (PMID: 17510385) and in in vitro assays (PMID: 23403630, PMID: 17510385, PMID: 20533529). | |
| A589D | missense | unknown | MLH1 A589D lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). The functional effect of A589D is conflicting, as it has been reported to result in a loss of mismatch repair activity in one study (PMID: 20020535), but in another study to have proficient mismatch repair activity in in vitro assays (PMID: 16083711), and demonstrates altered subcellular localization and reduced protein expression compared to wild-type Mlh1 (PMID: 21120944). | |
| A619P | missense | loss of function | MLH1 A619P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). A619P confers a loss of function to Mlh1 as demonstrated by defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484) and in an in vitro assay (PMID: 30504929). | |
| A681T | missense | unknown | MLH1 A681T lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). The functional effect of A681T is conflicting, as it demonstrates decreased stability resulting in decreased expression of Mlh1 (PMID: 23403630, PMID: 36454741), but has no effect on Mlh1 expression in another study (PMID: 21120944), and demonstrates mismatch repair (MMR) activity similar to wild-type Mlh1 in culture (PMID: 21120944, PMID: 16083711, PMID: 23403630) and intermediate MMR activity in another study (PMID: 31881334), and therefore, its effect on Mlh1 protein function is unknown. | |
| A92T | missense | unknown | MLH1 A92T lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A92T has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| C233R | missense | unknown | MLH1 C233R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). C233R has been identified in sequencing studies (PMID: 34513290), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| C39R | missense | loss of function - predicted | MLH1 C39R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). C39R demonstrates no splicing defects but leads to reduced Mlh1 and Pms2 expression and decreased mismatch repair activity in culture (PMID: 36054288), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| C77R | missense | loss of function | MLH1 C77R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). C77R confers a loss of function to the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in vitro assay, reduced localization with Pms2 (PMID: 16083711), and reduced protein expression as compared to wild-type (PMID: 21120944). | |
| C77Y | missense | loss of function - predicted | MLH1 C77Y lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). C77Y results in decreased mismatch repair (MMR) activity in an in vitro assay (PMID: 17510385), and decreased interaction with Pms2 and Exo1 in a yeast two-hybrid assay (PMID: 12810663), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| D132H | missense | unknown | MLH1 D132H lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). The functional effect of D132H is conflicting as it results in stable expression of Mlh1 and Pms2 and mismatch repair activity comparable to wild-type in culture (PMID: 36054288), in yeast assays, and in an in vitro assay (PMID: 17510385) but results in reduced ATPase activity compared to wild-type in the context of an N-terminal Mlh1 construct (PMID: 15184898). | |
| D304G | missense | loss of function - predicted | MLH1 D304G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D304G results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| D304V | missense | loss of function | MLH1 D304V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D304V results in a loss of mismatch repair (MMR) activity in an in vitro assay (PMID: 17510385) and in cell culture (PMID: 31784484), and a loss of Pms2 interaction in a yeast two-hybrid assay (PMID: 21952876). | |
| D41G | missense | loss of function - predicted | MLH1 D41G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D41G demonstrated aberrant splicing in one study (PMID: 15300854) and no splicing defects in another study (PMID: 26247049), but results in loss of protein expression compared to wild-type in culture, loss of mismatch repair activity in an in vitro assay (PMID: 23403630) and in a yeast assay (PMID: 15475387), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| D41H | missense | loss of function | MLH1 D41H lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D41H results in stable expression of Mlh1, Pms2, Msh2, and Msh6 in patient samples (PMID: 25060679) and variable expression in culture (PMID: 36054288, PMID: 25060679, PMID: 23403630) but leads to loss of mismatch repair activity in in vitro assays (PMID: 23403630, PMID: 25060679), loss of DNA damage response signaling (PMID: 36054288), and microsatellite instability in patient samples (PMID: 25060679). | |
| D41N | missense | unknown | MLH1 D41N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D41N has been identified in sequencing studies (PMID: 25233892), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| D41Y | missense | unknown | MLH1 D41Y lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D41Y has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| D450Ifs*41 | frameshift | loss of function - predicted | MLH1 D450Ifs*41 indicates a shift in the reading frame starting at amino acid 450 and terminating 41 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), D450Ifs*41 is predicted to lead to a loss of Mlh1 protein function. | |
| D485E | missense | unknown | MLH1 D485E lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). D485E results in mismatch repair (MMR) activity comparable to wild-type Mlh1 in yeast assays (PMID: 17510385) and reduced interaction with Pms2 in a yeast-two-hybrid assay (PMID: 21952876), but leads to reduced MMR in an in vitro assay (PMID: 17510385), and therefore, its effect on Mlh1 protein function is unknown. | |
| D601G | missense | no effect - predicted | MLH1 D601G lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). D601G results in protein expression of Mlh1 (PMID: 23403630, PMID: 20533529) and Pms2 (PMID: 20533529) comparable to wild-type in culture and mismatch repair activity comparable to wild-type in in vitro assays (PMID: 23403630, PMID: 20533529), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| D631H | missense | unknown | MLH1 D631H lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). D631H has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| D63E | missense | loss of function | MLH1 D63E lies within an ATP binding domain within the ATPase domain of the Mlh1 protein (PMID: 22753075). D63E confers a loss of function to the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in vitro assay, reduced localization with Pms2 (PMID: 16083711), and decreased protein expression as compared to wild-type (PMID: 21120944). | |
| D63N | missense | loss of function - predicted | MLH1 D63N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D63N demonstrates no splicing defects but results in reduced Pms2 and Mlh1 expression and decreased mismatch repair activity in culture (PMID: 36054288), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| D72Y | missense | unknown | MLH1 D72Y lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D72Y has been identified in sequencing studies (PMID: 22941189), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| D737V | missense | unknown | MLH1 D737V lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). D737V has been identified in sequencing studies (PMID: 23760103), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| D748A | missense | no effect - predicted | MLH1 D748A does not lie within any known functional domains of the Mlh1 protein (UniProt.org). D748A results in Mlh1 and Pms2 expression comparable to wild-type and mismatch repair activity similar to wild-type in culture (PMID: 36054288), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| del | deletion | loss of function | MLH1 del indicates a deletion of the MLH1 gene. | |
| del exon4 | deletion | unknown | MLH1 del exon4 indicates a deletion of exon 4 of the MLH1 gene. | |
| del exon5 | deletion | unknown | MLH1 del exon5 indicates a deletion of exon 5 of the MLH1 gene. | |
| E102* | nonsense | loss of function - predicted | MLH1 E102* results in a premature truncation of the Mlh1 protein at amino acid 102 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), E102* is predicted to lead to a loss of Mlh1 protein function. | |
| E102D | missense | loss of function - predicted | MLH1 E102D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E102D is predicted to confer a loss of function to the Mlh1 protein, as demonstrated by decreased mismatch repair activity (MMR) in an in vitro assay (PMID: 17510385). | |
| E102K | missense | loss of function | MLH1 E102K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E102K retains mismatch repair (MMR) activity in yeast assays (PMID: 17510385) but results in loss of protein expression compared to wild-type in culture (PMID: 23403630), decreased MMR activity in in vitro assays (PMID: 23403630, PMID: 17510385), and potentially, aberrant splicing (PMID: 12183410). | |
| E13* | nonsense | loss of function - predicted | MLH1 E13* results in a premature truncation of the Mlh1 protein at amino acid 13 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), E13* is predicted to lead to a loss of Mlh1 protein function. | |
| E172K | missense | unknown | MLH1 E172K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E172K has been identified in the scientific literature (PMID: 27998968, PMID: 37296477), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| E199K | missense | unknown | MLH1 E199K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E199K has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| E199Q | missense | no effect - predicted | MLH1 E199Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E199Q results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| E227* | nonsense | loss of function - predicted | MLH1 E227* results in a premature truncation of the Mlh1 protein at amino acid 227 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), E227* is predicted to lead to a loss of Mlh1 protein function. | |
| E234G | missense | loss of function - predicted | MLH1 E234G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E234G results in Mlh1 and Pms2 expression and mismatch repair activity comparable to wild-type in culture (PMID: 36054288), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| E23D | missense | loss of function - predicted | MLH1 E23D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E23D results in Mlh1 expression and Pms2 interaction similar to wild-type (PMID: 31697235), but results in decreased mismatch repair (MMR) activity in an in vitro assay (PMID: 17510385), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| E268G | missense | no effect - predicted | MLH1 E268G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E268G results in Mlh1 and Pms2 expression comparable to wild-type in culture and mismatch repair activity comparable to wild-type Mlh1 in culture (PMID: 36054288), in two of three yeast assays, and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| E313* | nonsense | loss of function - predicted | MLH1 E313* results in a premature truncation of the Mlh1 protein at amino acid 313 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), E313* is predicted to lead to a loss of Mlh1 protein function. | |
| E319K | missense | unknown | MLH1 E319K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E319K has been identified in the scientific literature (PMID: 31187078), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| E34* | nonsense | loss of function - predicted | MLH1 E34* results in a premature truncation of the Mlh1 protein at amino acid 34 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), E34* is predicted to lead to a loss of Mlh1 protein function. | |
| E37K | missense | loss of function - predicted | MLH1 E37K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E37K results in a loss of mismatch repair activity (MMR) in an in vitro assay (PMID: 20020535), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| E460A | missense | no effect | MLH1 E460A lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). E460A demonstrates similar mismatch repair activity (MMR) in an in vitro assay, similar subcellular localization, and similar protein expression as compared to wild-type (PMID: 21120944). | |
| E523D | missense | no effect - predicted | MLH1 E523D lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E523D results in mismatch repair activity comparable to wild-type Mlh1 in yeast assays and in an vitro assay (PMID: 17510385) and retains methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| E578G | missense | unknown | MLH1 E578G lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E578G results in stable Pms2 and Mlh1 expression and mismatch repair activity comparable to wild-type in culture in one study (PMID: 36054288), but in others demonstrates a loss of mismatch repair activity in an in-vitro assay (PMID: 20020535) and loss of interaction with Pms2 (PMID: 11292842), and therefore, its effect on Mlh1 protein function is unknown. | |
| E605del | deletion | unknown | MLH1 E605del results in the deletion of an amino acid in the C-terminal dimerization domain of the Mlh1 protein at amino acid 605 (PMID: 22753075). E605del results in intermediate protein expression compared to wild-type in culture but demonstrates mismatch repair activity comparable to wild-type in an in vitro assay (PMID: 25477341), and therefore, its effect on Mlh1 protein function is unknown. | |
| E633Kfs*4 | frameshift | loss of function - predicted | MLH1 E633Kfs*4 indicates a shift in the reading frame starting at amino acid 633 and terminating four residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). E633Kfs*4 results in loss of interaction with Pms2 and Exo1 in a yeast-two-hybrid assay, reduced Pms2 expression in an in vitro assay (PMID: 12810663), and due to loss of the C-terminal domain (PMID: 16338176), is predicted to lead to a loss of Mlh1 protein function. | |
| E633_E663del | deletion | loss of function | MLH1 E633_E663del results in deletion of 31 amino acids within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein from aa 633 to aa 663 (PMID: 22753075). E633_E663del confers a loss of function on the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in vitro assay, reduced Pms2 interaction, altered subcellular localization, and reduced protein expression as compared to wild-type (PMID: 21120944). | |
| E663A | missense | loss of function - predicted | MLH1 E663A lies within the EXO1-interacting region and the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E663A results in decreased mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| E663D | missense | unknown | MLH1 E663D lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E663D results in mismatch repair activity comparable to wild-type in two of three yeast assays and in an in vitro assay (PMID: 17510385), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| E663G | missense | no effect | MLH1 E663G lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E663G results in Mlh1 (PMID: 23403630, PMID: 20533529) and Pms2 (PMID: 20533529) protein expression comparable to wild-type in culture and mismatch repair activity comparable to wild-type in yeast assays (PMID: 17510385) and in in vitro assays (PMID: 23403630, PMID: 20533529, PMID: 17510385). | |
| E703A | missense | unknown | MLH1 E703A lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E703A has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| E71del | deletion | loss of function | MLH1 E71del results in the deletion of an amino acid within the ATPase domain of the Mlh1 protein (PMID: 22753075) at amino acid 71. E71del confers a loss of function on the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in vitro assay and altered subcellular localization as compared to wild-type (PMID: 21120944). | |
| E754Q | missense | unknown | MLH1 E754Q does not lie within any known functional domains of the Mlh1 protein (UniProt.org). E754Q has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| F530Lfs*5 | frameshift | loss of function - predicted | MLH1 F530Lfs*5 indicates a shift in the reading frame starting at amino acid 530 and terminating 5 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), F530Lfs*5 is predicted to lead to a loss of Mlh1 protein function. | |
| F80V | missense | loss of function | MLH1 F80V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). F80V confers a loss of function on Mlh1 as indicated by reduced mismatch repair activity (MMR) relative to wild-type Mlh1 in in vitro assays (PMID: 16083711, PMID: 21120944, PMID: 17510385). | |
| G101D | missense | loss of function | MLH1 G101D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G101D confers a loss of function to Mlh1 as indicated by defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), and decreased MMR activity in yeast cells (PMID: 15475387). | |
| G101S | missense | loss of function - predicted | MLH1 G101S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G101S results in reduced mismatch repair activity relative to wild-type Mlh1 in an in vitro assay (PMID: 30504929), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| G101V | missense | loss of function | MLH1 G101V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G101V results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), decreased MMR activity in a yeast assay, and defective binding with Pms2 (PMID: 21404117). | |
| G244D | missense | loss of function - predicted | MLH1 G244D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G244D results in ATPase activity, accumulation at double-stranded DNA breaks, and micronuclei formation similar to wild-type Mlh1 in cell culture (PMID: 29544212), but decreased mismatch repair (MMR) activity in in vitro assays (PMID: 17510385, PMID: 11781295), loss of interaction with Pms2 and Exo1 in yeast two-hybrid assays and loss of repression activity in a yeast reporter assay (PMID: 12810663), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| G244V | missense | loss of function | MLH1 G244V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G244V demonstrates no splicing defects but results in reduced Mlh1 and Pms2 expression and decreased mismatch repair activity in culture (PMID: 36054288), in an in vitro assay, and in yeast assays (PMID: 17510385), and leads to loss of methylation sensitivity in culture (PMID: 30998989). | |
| G357A | missense | unknown | MLH1 G357A does not lie within any known functional domains of the Mlh1 protein (UniProt.org). G357A has been identified in sequencing studies (PMID: 22980975), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| G454R | missense | no effect - predicted | MLH1 G454R lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). G454R results in Mlh1 and Pms2 expression similar to wild-type in culture, mismatch repair activity comparable to wild-type in culture (PMID: 36054288), and retains methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| G532C | missense | unknown | MLH1 G532C lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). G532C has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| G54E | missense | loss of function | MLH1 G54E lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G54E results in reduced protein expression compared to wild-type Mlh1 in culture and decreased mismatch repair activity in yeast assays (PMID: 17510385) and in in vitro assays (PMID: 23403630, PMID: 17510385). | |
| G65D | missense | loss of function | MLH1 G65D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G65D retains interaction with Pms2 in culture (PMID: 18094436) but results in loss of protein expression compared to wild-type Mlh1 in culture and loss of mismatch repair activity in an in vitro assay (PMID: 23403630) and in a yeast assay (PMID: 15475387). | |
| G67R | missense | loss of function | MLH1 G67R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G67R confers a loss of function to the Mlh1 protein as demonstrated by a reduced expression of Pms2 and Mlh1 in culture, loss of mismatch repair activity (MMR) in culture (PMID: 36054288) and in in vitro assays (PMID: 20020535, PMID: 17510385, PMID: 31881334), altered subcellular localization, and reduced protein expression compared to wild-type Mlh1 (PMID: 21120944). | |
| G67W | missense | loss of function | MLH1 G67W lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G67W results in decreased mismatch repair activity (MMR) in an in vitro assay (PMID: 17510385) and in cultured cells (PMID: 31784484). | |
| H109D | missense | unknown | MLH1 H109D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H109D has been identified in sequencing studies (PMID: 22722839), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| H109P | missense | loss of function - predicted | MLH1 H109P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H109P results in a loss of mismatch repair activity of in an in vitro assay (PMID: 20020535), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| H109Q | missense | no effect - predicted | MLH1 H109Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H109Q results in protein expression comparable to wild-type in culture and mismatch repair activity comparable to wild-type in an in vitro assay (PMID: 23403630), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| H112D | missense | unknown | MLH1 H112D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H112D retains ATPase activity in in vitro analyses (PMID: 17135187, PMID: 29544212) leading to functional subcellular localization, recruitment to double strand breaks, ability to suppress interstitial telomeric sequences and genomic instability (PMID: 29544212) and retains binding to Pms2 but impairs interaction with Msh2-Msh6-DNA complex in culture and leads to loss of mismatch repair activity (MMR) in an in vitro analysis in one study (PMID: 17135187), but in another results in normal expression of Pms2 and Mlh1 and MMR activity comparable to wild-type in culture (PMID: 36054288), and therefore, its effect on Mlh1 protein function is unknown. | |
| H112Q | missense | unknown | MLH1 H112Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H112Q results in protein expression comparable to wild-type in culture and moderately decreased mismatch repair activity compared to wild-type in an in vitro assay (PMID: 29520894), and therefore, its effect on Mlh1 protein function is unknown. | |
| H264Lfs*2 | frameshift | loss of function - predicted | MLH1 H264Lfs*2 indicates a shift in the reading frame starting at amino acid 264 and terminating 2 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). H264Lfs*2 results in aberrant splicing and deficient mismatch repair activity in an in vitro assay (PMID: 32849802), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| H264Y | missense | loss of function - predicted | MLH1 H264Y lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H264Y results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| H308P | missense | loss of function - predicted | MLH1 H308P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H308P results in aberrant splicing and deficient mismatch repair activity in an in vitro assay (PMID: 32849802), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| H315Y | missense | unknown | MLH1 H315Y lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H315Y has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| H329P | missense | unknown | MLH1 H329P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H329P results in altered subcellular localization and reduced protein expression (PMID: 21120944), decreased mismatch repair (MMR) activity in yeast (PMID: 17510385), but demonstrates proficient mismatch repair activity (PMID: 21120944), and ATPase activity, suppression of interstitial telomeric sequences, and localization to double-strand break sites (DSBs) similar to wild-type Mlh1 in cultured cells (PMID: 29544212), and therefore, its effect on Mlh1 protein function is unknown. | |
| H543R | missense | unknown | MLH1 H543R lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). H543R has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| H718Y | missense | no effect | MLH1 H718Y lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). H718Y results in Mlh1 and Pms2 expression comparable to wild-type Mlh1 in culture (PMID: 23403630, PMID: 36054288), stable mismatch repair activity in two of three yeast assays (PMID: 17510385), and in an in vitro assay (PMID: 17510385), and in culture (PMID: 36054288), low mutation rate in one of two yeast assays (PMID: 17210669), and retains binding to Pms2 and Exo1 in a yeast-two-hybrid assay (PMID: 12810663). | |
| H733Qfs*14 | frameshift | loss of function - predicted | MLH1 H733Qfs*14 indicates a shift in the reading frame starting at amino acid 733 and terminating 14 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). H733Qfs*14 results in reduced Pms2 expression compared to wild-type Mlh1 in an in vitro assay, loss of interaction with Pms2 and Exo1 in a yeast-two-hybrid assay (PMID: 12810663), loss of Mlh1 and Pms2 expression, microsatellite instability in a patient sample (PMID: 31028081), and due to loss of the C-terminal domain (PMID: 16338176), is predicted to lead to a loss of Mlh1 protein function. | |
| hypermethylation | unknown | unknown | MLH1 hypermethylation indicates an increased methylation of the MLH1 gene. However, the mechanism causing the hypermethylation is unspecified. | |
| I107R | missense | loss of function | MLH1 I107R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I107R confers a loss of function on the Mlh1 protein as demonstrated by reduced Pms2 and Mlh1 expression in culture, reduced mismatch repair activity in culture (PMID: 36054288) and an in vitro assay (PMID: 16083711), altered subcellular localization, and reduced protein expression compared to wild-type Mlh1 (PMID: 21120944). | |
| I190T | missense | unknown | MLH1 I190T lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I190T has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| I19F | missense | loss of function - predicted | MLH1 I19F lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I19F results in stable expression of Pms2 and Mlh1 but decreased mismatch repair activity in culture (PMID: 36054288), and therefore is predicted to lead to a loss of Mlh1 protein function. | |
| I219L | missense | no effect | MLH1 I219L lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I219L is a common polymorphism (PMID: 8872463, PMID: 16982745) with activity comparable to wild-type Mlh1, as demonstrated by binding to Pms2 and Exo1 comparable to wild-type in a yeast two hybrid assay (PMID: 12810663), interaction with Pms2 similar to wild-type in culture, sufficient mismatch repair (MMR) activity to provide methylation sensitivity in culture (PMID: 16982745), and MMR activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385). | |
| I219V | missense | no effect | MLH1 I219V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I219V is a common polymorphism with activity comparable to wild-type Mlh1 (PMID: 20020535) as demonstrated by functional mismatch repair activity in culture (PMID: 36054288) and in in vitro assays and protein expression comparable to wild-type Mlh1 (PMID: 21120944, PMID: 31881334, PMID: 23403630), and subcellular localization similar to wild-type (PMID: 21120944, PMID: 31881334). | |
| I25F | missense | unknown | MLH1 I25F lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). The functional effect of I25F is conflicting as it results in mismatch repair (MMR) activity comparable to wild-type Mlh1 in yeast assays (PMID: 17510385), but in another study results in increased mutation rate in yeast assays (PMID: 17210669) and decreased MMR activity in an in vitro assay (PMID: 17510385). | |
| I25T | missense | no effect - predicted | MLH1 I25T lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I25T results in mismatch repair (MMR) activity similar to wild-type in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| I262M | missense | unknown | MLH1 I262M lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I262M has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| I276R | missense | loss of function - predicted | MLH1 I276R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I276R results in Mlh1 and Pms2 expression comparable to wild-type but demonstrates reduced mismatch repair activity in culture (PMID: 36054288), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| I32V | missense | unknown | MLH1 I32V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I32V retains interaction with Pms2 and Exo1 in a yeast-two-hybrid assay (PMID: 12810663) and demonstrates reduced interaction with Mre11 by yeast-two-hybrid assay and cell culture (PMID: 18373977), but has not been fully biochemically characterized and therefore, the effect on Mlh1 protein function is unknown. | |
| I330del | deletion | loss of function | MLH1 I330del results in the deletion of an amino acid in the ATPase domain of the Mlh1 protein (PMID: 22753075) at amino acid 330. I330del confers a loss of function on the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in-vitro assay and altered subcellular localization as compared to wild-type (PMID: 21120944). | |
| I501del | deletion | no effect - predicted | MLH1 I501del results in the deletion of an amino acid in the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein at amino acid 501 (PMID: 22753075). I501del results in protein expression comparable to wild-type in culture and mismatch repair activity comparable to wild-type in an in vitro assay (PMID: 29520894), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| I565F | missense | loss of function - predicted | MLH1 I565F lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). I565F results in Mlh1 expression but loss of Msh2 and Msh6 expression in patient samples (PMID: 15943554) and reduced mismatch repair activity in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| I565M | missense | unknown | MLH1 I565M lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). I565M has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| I565T | missense | unknown | MLH1 I565T lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). I565T retains methylation sensitivity in culture (PMID: 30998989), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| I630S | missense | unknown | MLH1 I630S lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). I630S has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| I655T | missense | no effect - predicted | MLH1 I655T lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). I655T results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| I655V | missense | no effect - predicted | MLH1 I655V lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). I655V results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| I68N | missense | loss of function - predicted | MLH1 I68N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I68N results in decreased mismatch repair (MMR) activity in in vitro assays (PMID: 17510385, PMID: 15475387), loss of interaction with Pms2 and Exo1 in yeast two-hybrid assays, and loss of repression activity in a yeast reporter assay (PMID: 12810663), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| I68V | missense | no effect - predicted | MLH1 I68V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). I68V results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| inact mut | unknown | loss of function | MLH1 inact mut indicates that this variant results in a loss of function of the Mlh1 protein. However, the specific amino acid change has not been identified. | |
| K118N | missense | loss of function - predicted | MLH1 K118N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). K118N results in increased mutation rates indicating a loss of mismatch repair activity compared to Mlh1 in parent strains of yeast-human hybrids (PMID: 15475387), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| K195* | nonsense | loss of function | MLH1 K195* results in a premature truncation of the Mlh1 protein at amino acid 195 of 756 (PMID: 22753075). K195* confers a loss of function to the Mlh1 protein due to the loss of the C-terminal domain (PMID: 16338176), loss of protein expression compared to wild-type in culture, and loss of mismatch repair activity in an in vitro assay (PMID: 25477341). | |
| K241N | missense | unknown | MLH1 K241N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). K241N has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| K254N | missense | unknown | MLH1 K254N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). K254N has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| K286Q | missense | no effect - predicted | MLH1 K286Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). K286Q results in Mlh1 and Pms2 expression comparable to wild-type in culture and mismatch repair activity comparable to wild-type in culture (PMID: 36054288), in two of three yeast assays, and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| K443Q | missense | no effect | MLH1 K443Q lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). K443Q is predicted to be benign by in silico analyses (PMID: 20020535, PMID: 22753075) and has mismatch repair (MMR) activity similar to wild-type Mlh1 (PMID: 16083711, PMID: 20020535, PMID: 21120944) in in vitro assays. | |
| K618A | missense | unknown | MLH1 K618A lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). The functional effect of K618A is conflicting, as it results in mismatch repair activity similar to wild-type Mlh1 in in vitro assays (PMID: 16083711, PMID: 20020535, PMID: 21120944) and stable microsatellites (PMID: 36054288), but has also been reported to have reduced binding to Pms2 (PMID: 10037723), reduced Pms2 and Mlh1 expression (PMID: 36054288), decreased mismatch repair activity in culture (PMID: 31784484), and to cause reduced cell line viability (PMID: 16982745). | |
| K618del | deletion | loss of function - predicted | MLH1 K618del results in the deletion of an amino acid in the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein at amino acid 618 (PMID: 22753075). K618del (reported as K616del) results in altered subcellular localization, reduced protein expression compared to wild-type Mlh1 (PMID: 21120944), and reduced interaction with Pms2 and Exo1 in a yeast two-hybrid assay (PMID: 12810663), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| K618E | missense | unknown | MLH1 K618E lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). K618E has been identified in the scientific literature (PMID: 30998989), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| K618R | missense | unknown | MLH1 K618R lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). K618R results in reduced protein expression in patient samples (PMID: 11807791, PMID: 19863800) and is associated with microsatellite instability in a patient sample (PMID: 19863800), and results in intermediate Mlh1 expression in culture, interaction with Pms2 similar to wild-type in a yeast-two-hybrid assay (PMID: 21404117), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| K618T | missense | unknown | MLH1 K618T lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). The functional effect of K618T is conflicting, as it has been shown to have mismatch repair activity and Pms2 binding similar to wild-type Mlh1 (PMID: 16083711, PMID: 22753075, PMID: 21120944), but has also been shown to have significantly reduced binding to Pms2 in in vitro assays (PMID: 10037723), and decreases MLH1 foci and chromosomal crossover during meiosis resulting in increased aneuploidy in a mouse model (PMID: 34408140), and therefore, its effect on Mlh1 protein function is unknown. | |
| K751R | missense | no effect - predicted | MLH1 K751R does not lie within any known functional domains of the Mlh1 protein (UniProt.org). K751R results in Pms2 stabilization similar to wild-type Mlh1 (PMID: 16338176), a mutation rate comparable to wild-type in yeast assays (PMID: 17210669), and results in mismatch repair (MMR) activity similar to wild-type in an in vitro assay and yeast assays (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| K84E | missense | loss of function | MLH1 K84E lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). K84E confers a loss of function to the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in in vitro assays (PMID: 16083711, PMID: 21120944) and in cultutred cells (PMID: 31784484). | |
| L135V | missense | no effect - predicted | MLH1 L135V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). Results in stable expression of Mlh1 and Pms2 and mismatch repair activity comparable to wild-type in culture (PMID: 36054288), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| L155P | missense | unknown | MLH1 L155P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). L155P has been identified in sequencing studies (PMID: 24686850), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| L155R | missense | loss of function | MLH1 L155R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). L155R confers a loss of function on the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in-vitro assay (PMID: 16083711), altered subcellular localization, and reduced protein expression as compared to wild-type (PMID: 21120944). | |
| L260F | missense | loss of function - predicted | MLH1 L260F lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). L260F demonstrates no splicing defects (PMID: 18561205) but results in reduced methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| L272V | missense | no effect - predicted | MLH1 L272V lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). L272V results in mismatch repair activity comparable to wild-type Mlh1 in yeast assays and in an in vitro assay (PMID: 17510385) and demonstrates a low mutation rate in one of two yeast assays (PMID: 17210669), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| L507* | nonsense | loss of function - predicted | MLH1 L507* results in a premature truncation of the Mlh1 protein at amino acid 507 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), L507* is predicted to lead to a loss of Mlh1 protein function. | |
| L507F | missense | no effect - predicted | MLH1 L507F lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L507F results in protein expression and subcellular localization comparable to wild-type in culture and mismatch repair activity comparable to wild-type in an in vitro assay (PMID: 25477341), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| L549P | missense | loss of function | MLH1 L549P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L549P results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484) and loss of Pms2 binding in a yeast two-hybrid assay (PMID: 18094436). | |
| L550I | missense | unknown | MLH1 L550I lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L550I has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| L550P | missense | unknown | MLH1 L550P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). The functional effect of L550P is conflicting, as it results in a loss of mismatch repair activity in an in vitro assay (PMID: 20020535) and in cell culture (PMID: 31784484), but also demonstrates mismatch repair activity, localization, and protein expression to similar levels as wild-type Mlh1 in culture (PMID: 16083711, PMID: 21120944). | |
| L555P | missense | loss of function | MLH1 L555P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L555P results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484) and in an in vitro assay (PMID: 23712482). | |
| L559R | missense | loss of function | MLH1 L559R lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L559R confers a loss of function to the Mlh1 protein as demonstrated by decreased protein expression and disruption of the interaction between Mlh1 and Pms2 (PMID: 16724012). | |
| L574P | missense | loss of function | MLH1 L574P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L574P confers a loss of function on Mlh1 as indicated by decreased interaction with Pms2 in a yeast two-hybrid assay (PMID: 12810663), and decreased mismatch repair (MMR) activity compared to wild-type in an in vitro assay (PMID: 17510385). | |
| L582F | missense | loss of function - predicted | MLH1 L582F lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L582F results in impaired mismatch repair activity (MMR) in an in vitro assay (PMID: 20020535), and decreased binding to Pms2 and Exo1 in yeast two-hybrid assays (PMID: 12810663), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| L582P | missense | unknown | MLH1 L582P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L582P results in loss of Mlh1, Pms2, Msh6 and is associated with microsatellite instability in patient samples (PMID: 36387226), reduced Mlh1 expression in culture, and reduced interaction with Pms2 in a yeast-two-hybrid assay (PMID: 21404117), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| L582V | missense | loss of function - predicted | MLH1 L582V lies within the EXO1-interacting region and C-terminal dimerization domain of the MLH1 protein (PMID: 22753075). L582V results in repression activity similar to wild-type Mlh1 in a yeast reporter assay, but results in decreased Exo1 and Pms2 interaction in a yeast two-hybrid assay, decreased Pms2 binding in an in vitro assay (PMID: 12810663), and decreased MMR activity in an in vitro assay (PMID: 17510385), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| L588P | missense | loss of function | MLH1 L588P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L588P results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484) and decreased MMR activity in an in vitro assay (PMID: 17510385). | |
| L588R | missense | unknown | MLH1 L588R lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L588R has been identified in sequencing studies (PMID: 27294619), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| L590I | missense | unknown | MLH1 L590I lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L590I has been identified in sequencing studies (PMID: 27294619), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| L607H | missense | unknown | MLH1 L607H lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L607H results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), microsatellite stability in patient samples (PMID: 11839723), and retains interaction with Pms2, but leads to loss of interaction with Fancj, increased sensitivity to cross-linking agents, and reduces methylation sensitivity in the presence of a methyltransferase (PMID: 20978114), and therefore, the effect on Mlh1 protein function is unknown. | |
| L622H | missense | unknown | MLH1 L622H lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L622H results in decreased Mlh1 protein stability and expression (PMID: 23403630, PMID: 20858721, PMID: 31881334), and demonstrates both proficient mismatch repair (MMR) activity in some assays (PMID: 17510385, PMID: 23403630), and deficient MMR activity (PMID: 31881334), and therefore, its effect on Mlh1 protein function is unknown. | |
| L622P | missense | loss of function - predicted | MLH1 L622P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L622P results in reduced methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| L636P | missense | loss of function - predicted | MLH1 L636P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L636P results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| L653R | missense | loss of function - predicted | MLH1 L653R lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L653R results in decreased mismatch repair (MMR) activity compared to wild-type Mlh1 in an in vitro assay (PMID: 17510385), and reduced interaction with Pms2 in a yeast two-hybrid assay (PMID: 21952876), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| L658I | missense | unknown | MLH1 L658I lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L658I has been identified in sequencing studies (PMID: 27294619), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| L676P | missense | loss of function - predicted | MLH1 L676P lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L676P retains subcellular localization and interaction with Pms2 comparable to wild-type (PMID: 26437257) but demonstrates decreased protein expression compared to wild-type in culture and decreased mismatch repair activity in an in vitro assay (PMID: 29520894), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| L676R | missense | loss of function | MLH1 L676R lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L676R results in loss of Mlh1 protein expression compared to wild-type in culture and loss of mismatch repair activity in yeast assays (PMID: 17510385) and in in vitro assays (PMID: 17510385, PMID: 23403630). | |
| L729V | missense | no effect - predicted | MLH1 L729V lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L729V results in interaction with Pms2 and Exo1 similar to wild-type in a yeast-two-hybrid assay (PMID: 12810663) and mismatch repair activity similar to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| L73P | missense | loss of function | MLH1 L73P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). L73P demonstrates no splicing defects (PMID: 36054288) and does not alter subcellular localization of Mlh1 and Pms2 (PMID: 22736432) but leads to reduced Mlh1 and Pms2 expression in culture (PMID: 36054288, PMID: 22736432), decreased mismatch repair activity compared to wild-type Mlh1 in culture (PMID: 36054288), in a yeast assay (PMID: 15475387), and in an in vitro analysis, and is associated with microsatellite instability in a patient sample (PMID: 22736432). | |
| L749* | nonsense | loss of function | MLH1 L749* results in a premature truncation of the Mlh1 protein at amino acid 749 of 756 (UniProt.org). L749* results in a loss of the C-terminal domain and demonstrates decreased stability of the Mlh1/Pms2 heterodimer, increased mutation rates, and failure to induce cell-cycle arrest of drug-induced MLH1 L749*-expressing cells in culture (PMID: 16338176). | |
| L749P | missense | loss of function | MLH1 L749P does not lie within any known functional domains of the Mlh1 protein (UniProt.org). L749P confers a loss of function to the Mlh1 protein as demonstrated by protein loss via immunostaining, inefficient mismatch repair activity (PMID: 14504054, PMID: 20533529), and has also been reported to have decreased protein expression (PMID: 21286667). | |
| L85P | missense | loss of function - predicted | MLH1 L85P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). L85P results in reduced methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| LOH | deletion | unknown | MLH1 LOH indicates the loss of one parental copy of the MLH1 gene, resulting in loss of heterozygosity. | |
| loss | unknown | loss of function | MLH1 loss indicates loss of the MLH1 gene, mRNA, and protein. | |
| M35R | missense | loss of function - predicted | MLH1 M35R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). M35R results in decreased mismatch repair (MMR) activity in in vitro assays (PMID: 17510385), loss of interaction with Pms2 and Exo1 in yeast two-hybrid assays, and decreased repression activity in a yeast reporter assay (PMID: 12810663), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| M383V | missense | unknown | MLH1 M383V does not lie within any known functional domains of the Mlh1 protein (UniProt.org). M383V has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| M524I | missense | unknown | MLH1 M524I lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (UniProt.org). M524I has been identified in the scientific literature (PMID: 31273885, PMID: 35932099), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| M587Hfs*6 | frameshift | loss of function - predicted | MLH1 M587Hfs*6 indicates a shift in the reading frame starting at amino acid 587 and terminating six residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). M587Hfs*6 is associated with microsatellite instability in patient samples (PMID: 34638295, PMID: 37773826), reduced expression of Mlh1 and Pms2 in a patient sample (PMID: 37773826), results in loss of interaction with Pms2 and Exo1 in a yeast-two-hybrid assay, and reduced Pms2 expression in an in vitro assay (PMID: 12810663), and due to loss of the C-terminal domain (PMID: 16338176), is predicted to lead to a loss of Mlh1 protein function. | |
| M587V | missense | unknown | MLH1 M587V lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (UniProt.org). M587V has been identified in sequencing studies (PMID: 18206535), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| mutant | unknown | unknown | MLH1 mutant indicates an unspecified mutation in the MLH1 gene. | |
| N187Y | missense | unknown | MLH1 N187Y lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). N187Y has been identified in sequencing studies (PMID: 21720365), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| N215S | missense | unknown | MLH1 N215S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). N215S demonstrates no splicing defects (PMID: 18561205) and retains methylation sensitivity in culture (PMID: 30998989), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| N338S | missense | no effect - predicted | MLH1 N338S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). N338S retains mismatch repair activity relative to wild-type Mlh1 in in vitro assays (PMID: 29520894), and results in protein stabiility, DNA damage response signaling, and DNA repair activity similar to wild-type Mlh1 in cultured cells (PMID: 36054288), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| N38D | missense | loss of function | MLH1 N38D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). N38D confers a loss of Mlh1 protein function, as indicated by a loss of mismatch repair (MMR) activity in an in vitro assay (PMID: 17510385) and in cultured cells (PMID: 31784484). | |
| N38H | missense | loss of function - predicted | MLH1 N38H lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). N38H demonstrates a loss of mismatch repair activity in an in vitro assay (PMID: 20020535), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| N38K | missense | loss of function - predicted | MLH1 N38K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). N38K results in a loss of mismatch repair activity in an in vitro assay (PMID: 20020535), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| N551S | missense | unknown | MLH1 N551S lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). N551S results in splicing similar to wild-type Mlh1 and proficient mismatch repair activity in an in vitro assay (PMID: 32849802), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| N551T | missense | unknown | MLH1 N551T lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). N551T results in decreased Mlh1 protein stability and expression (PMID: 23403630), and decreased mismatch repair activity in culture in one study (PMID: 31784484), but also demonstrates mismatch repair activity comparable to wild-type Mlh1 in other studies (PMID: 17510385, PMID: 23403630), and therefore, its effect on Mlh1 protein function is unknown. | |
| N64S | missense | unknown | MLH1 N64S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). The functional effect of N64S is conflicting as it results in reduced Pms2 and Mlh1 expression in culture (PMID: 36054288, PMID: 21404117), reduced interaction with Pms2 in a yeast-two-hybrid assay (PMID: 21404117), loss of mismatch repair (MMR) activity in two of three yeast assays, reduced MMR activity in vitro (PMID: 17510385) and in culture (PMID: 17135187), and increased mutation rate in yeast assays (PMID: 17210669), but in other studies results in stabilization of Pms2 in culture (PMID: 17135187), MMR activity comparable to wild-type in culture, and demonstrates no splicing defects (PMID: 36054288). | |
| negative | unknown | loss of function | MLH1 negative indicates a lack of expression of the MLH1 mRNA and/or protein. | |
| P141A | missense | no effect - predicted | MLH1 P141A lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). P141A results in protein expression comparable to wild-type in culture and mismatch repair activity similar to wild-type in an in vitro assay (PMID: 29520894), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| P28L | missense | loss of function | MLH1 P28L lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). P28L is predicted to lead to loss of Mlh1 function in in silico analyses, results in loss of mismatch repair activity (MMR) in in vitro assays (PMID: 22753075, PMID: 17510385), and has reduced protein expression as compared to wild-type (PMID: 21120944). | |
| P403S | missense | no effect - predicted | MLH1 P403S does not lie within any known functional domains of the Mlh1 protein (UniProt.org). P403S is predicted to be benign in in silico analyses (PMID: 22753075) and has mismatch repair activity similar to wild-type Mlh1 in an in vitro assay (PMID: 20020535), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| P496L | missense | no effect - predicted | MLH1 P496L lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P496L results in mismatch repair activity comparable to wild-type in yeast assays and in an vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| P578_E632del | deletion | loss of function | MLH1 P578_E632del results in the deletion of 54 amino acids within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein from aa 578 to aa 632 (UniProt.org). P578_E632del confers a loss of function on the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in vitro assay and reduced Pms2 interaction as compared to wild-type (PMID: 21120944). | |
| P581L | missense | no effect - predicted | MLH1 P581L lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P581L results in decreased Pms2 binding in a yeast two-hybrid assay (PMID: 18094436), but demonstrates mismatch repair activity similar to wild-type Mlh1 in cultured cells as indicated by DNA slippage error rates and methylation-induced mutagenesis rates (PMID: 31784484), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| P603R | missense | no effect - predicted | MLH1 P603R lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P603R results in mismatch repair activity comparable to wild-type in yeast assays and in an vitro assay (PMID: 17510385), protein expression comparable to wild-type in culture, and interaction with Pms2 similar to wild-type in a yeast-two-hybrid assay (PMID: 21404117), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| P640L | missense | loss of function - predicted | MLH1 P640L lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P640L results in decreased mismatch repair (MMR) in cultured cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| P640S | missense | loss of function - predicted | MLH1 P640S lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P640S results in decreased mismatch repair (MMR) in cultured cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| P640T | missense | loss of function - predicted | MLH1 P640T lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P640T results in loss of mismatch repair (MMR) activity in yeast assays and reduced MMR activity in an in vitro assay (PMID: 17510385), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| P648L | missense | unknown | MLH1 P648L lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P648L results in decreased binding to Exo1 and Pms2 (PMID: 22753075) and reduced Mlh1 protein expression in cell culture (PMID: 21120944, PMID: 16083711), but demonstrates variable mismatch repair activity in in vitro assays (PMID: 20020535, PMID: 16083711, PMID: 22753075), and therefore, its effect on Mlh1 protein function is unknown. | |
| P648S | missense | unknown | MLH1 P648S lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P648S results in decreased Mlh1 protein expression in cell culture (PMID: 21120944, PMID: 16083711), and reduced Pms2 binding in an in vitro assay (PMID: 16724012), but demonstrates proficient mismatch repair activity in in vitro assays (PMID: 21120944, PMID: 16083711, PMID: 15139004), and therefore, its effect on Mlh1 protein function is unknown. | |
| P654L | missense | loss of function | MLH1 P654L lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P654L confers a loss of function to the Mlh1 protein as indicated by its prediction to be pathogenic based on an in silico analysis (PMID: 22753075), a loss of mismatch repair activity (MMR) in an in-vitro assay (PMID: 20020535), altered subcellular localization, and reduced protein expression as compared to wild-type (PMID: 21120944). | |
| P709Q | missense | unknown | MLH1 P709Q lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). P709Q has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| positive | unknown | unknown | MLH1 positive indicates the presence of the MLH1 gene, mRNA, and/or protein. | |
| Q26R | missense | unknown | MLH1 Q26R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). Q26R has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| Q391R | missense | unknown | MLH1 Q391R does not lie within any known functional domains of the Mlh1 protein (UniProt.org). Q391R has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| Q48E | missense | unknown | MLH1 Q48E lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). Q48E has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| Q48P | missense | unknown | MLH1 Q48P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). Q48P results in loss of Mlh1 expression and is associated with microsatellite instability in patient samples (PMID: 22395473) and loss of Mlh1 expression in cultured cells and reduced interaction with Pms2 in a yeast-two-hybrid assay (PMID: 21404117), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| Q542L | missense | loss of function | MLH1 Q542L lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). Q542L maintains interaction with Pms2 (PMID: 12810663), but results in reduced Pms2 and Mlh1 expression (PMID: 36054288) and decreased mismatch repair activity in an in vitro assay (PMID: 17510385) and in cell culture (PMID: 31784484, PMID: 36054288). | |
| Q562P | missense | unknown | MLH1 Q562P lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). Q562P results in reduced Mlh1 protein expression in culture and reduced interaction with Pms2 in a yeast-two-hybrid assay (PMID: 21404117), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| Q60P | missense | loss of function - predicted | MLH1 Q60P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). Q60P results in partial loss of DNA mismatch repair activity in a yeast assay (PMID: 15475387), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| Q689R | missense | no effect | MLH1 Q689R lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). Q689R has no effect on the Mlh1 protein function as demonstrated by stable Pms2 and Mlh1 expression and functional mismatch repair activity in culture (PMID: 36054288) and in in vitro assays (PMID: 21404117, PMID: 17510385). | |
| Q701K | missense | unknown | MLH1 Q701K lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). Q701K results in reduced Mlh1 expression and altered subcellular localization in patient samples (PMID: 22136435), and decreased interaction with Pms2 in a yeast assay and in culture (PMID: 18094436), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| R100* | nonsense | loss of function - predicted | MLH1 R100* results in a premature truncation of the Mlh1 protein at amino acid 100 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), R100* is predicted to lead to a loss of Mlh1 protein function. | |
| R100P | missense | loss of function | MLH1 R100P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R100P results in Pms2 and Mlh1 expression comparable to wild-type in culture (PMID: 36054288) but confers a loss of function to the Mlh1 protein as demonstrated by loss of mismatch repair (MMR) activity in an in vitro assay (PMID: 17510385) and in culture (PMID: 36054288), increased Mlh1 degradation, and decreased Pms2 interaction compared to wild-type in cell culture (PMID: 31697235). | |
| R100Q | missense | loss of function | MLH1 R100Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R100Q results in Mlh1 and Pms2 expression comparable to wild-type Mlh1 but leads to reduced mismatch repair activity in culture (PMID: 36054288) and in a yeast assay (PMID: 15475387). | |
| R127K | missense | loss of function - predicted | MLH1 R127K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R127K results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| R182G | missense | unknown | MLH1 R182G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). The functional effect of R182G is conflicting as it results in mismatch repair activity comparable to wild-type Mlh1 in yeast assays and in an in vitro assay (PMID: 17510385) but leads to alternative splicing and loss of Mlh1 and Pms2 in a patient sample (PMID: 22773173). | |
| R217C | missense | unknown | MLH1 R217C lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). The functional effect of R217C is conflicting, as it demonstrates mismatch repair activity similar to wild-type Mlh1 in a cell based assay (PMID: 11781295), but also results in impaired interaction with Pms2 (PMID: 27173243), and therefore, its effect on Mlh1 protein function is unknown. | |
| R226* | nonsense | loss of function - predicted | MLH1 R226* results in a premature truncation of the Mlh1 protein at amino acid 226 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), R226* is predicted to lead to a loss of Mlh1 protein function. | |
| R226L | missense | loss of function - predicted | MLH1 R226L lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R226L results in reduced mismatch repair activity in two of three yeast assays and in an in vitro assay (PMID: 17510385) and demonstrates aberrant MLH1 splicing (PMID: 15300854), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| R226Q | missense | unknown | MLH1 R226Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R226Q results in a loss of exon 8 in patient samples, likely due to aberrant splicing (PMID: 16341550, PMID: 15300854), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| R265C | missense | loss of function | MLH1 R265C lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R265C may confer a partial loss of function to the Mlh1 protein as indicated by reduced mismatch repair (MMR) activity in in-vitro assays (PMID: 20020535, PMID: 17510385) and reduced ability to interact with Pms2 (PMID: 21952876). | |
| R265H | missense | no effect | MLH1 R265H lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R265H results in protein expression comparable to wild-type in culture (PMID: 23403630) and mismatch repair activity comparable to wild-type in yeast assays (PMID: 17510385) and in in vitro assays (PMID: 11781295, PMID: 17510385, PMID: 23403630). | |
| R265P | missense | loss of function - predicted | MLH1 R265P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R265P results in intermediate protein expression compared to wild-type in culture but decreased mismatch repair activity in an in vitro assay (PMID: 29520894), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| R265S | missense | loss of function | MLH1 R265S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R265S results in reduced Pms2 and Mlh1 expression and loss of mismatch repair activity in culture (PMID: 36054288) and in an in vitro assay (PMID: 20020535) and demonstrates aberrant Mlh1 splicing (PMID: 36054288). | |
| R325W | missense | unknown | MLH1 R325W lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R325W has been identified in sequencing studies (PMID: 26000489), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| R385C | missense | no effect - predicted | MLH1 R385C does not lie within any known functional domains of the Mlh1 protein (UniProt.org). R385C results in Mlh1 protein expression level, DNA polymerase slippage rate, and methylation-damage-induced mutagenesis rate similar to wild-type Mlh1 in culture (PMID: 31784484), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| R389Q | missense | no effect - predicted | MLH1 R389Q does not lie within any known functional domains of Mlh1 protein (UniProt.org). R389Q results in similar mismatch repair (MMR) activity as wild-type Mlh1 in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| R389W | missense | unknown | MLH1 R389W does not lie within any known functional domains of the Mlh1 protein (UniProt.org). R389W has been identified in the scientific literature (PMID: 28642281), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| R474G | missense | no effect - predicted | MLH1 R474G lies within the EXO1-interacting region and bipartite NLS sequence of the Mlh1 protein (PMID: 22753075). R474G retains methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| R474P | missense | no effect - predicted | MLH1 R474P lies within the EXO1-interacting region and bipartite NLS sequence of the Mlh1 protein (PMID: 22753075). R474P results in Mlh1 and Pms2 expression similar to wild-type in culture and mismatch repair activity comparable to wild-type in culture (PMID: 36054288), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| R474Q | missense | no effect | MLH1 R474Q lies within the EXO1-interacting region and bipartite NLS sequence of the Mlh1 protein (PMID: 22753075). R474Q results in Mlh1 and Pms2 expression similar to wild-type Mlh1 in culture, mismatch repair activity comparable to wild-type in culture (PMID: 36054288), in yeast assays, and in an in vitro assay (PMID: 17510385), and retains methylation sensitivity in culture (PMID: 30998989). | |
| R474W | missense | no effect - predicted | MLH1 R474W lies within the EXO1-interacting region and bipartite NLS sequence of the Mlh1 protein (PMID: 22753075). R474W demonstrates no splicing defects (PMID: 18561205) and retains methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| R487* | nonsense | loss of function - predicted | MLH1 R487* results in a premature truncation of the Mlh1 protein at amino acid 487 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), R487* is predicted to lead to a loss of Mlh1 protein function. | |
| R487L | missense | unknown | MLH1 R487L lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). R487L has been identified in sequencing studies (PMID: 36531003), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| R497Gfs*11 | frameshift | loss of function - predicted | MLH1 R497Gfs*11 indicates a shift in the reading frame starting at amino acid 497 and terminating 11 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), R497Gfs*11 is predicted to lead to a loss of Mlh1 protein function. | |
| R498Efs*10 | frameshift | loss of function - predicted | MLH1 R498Efs*10 indicates a shift in the reading frame starting at amino acid 498 and terminating ten residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). R498Efs*10 results in loss of interaction with Pms2 and Exo1 in a yeast-two-hybrid assay, reduced Pms2 expression in an in vitro assay (PMID: 12810663), and due to loss of the C-terminal domain (PMID: 16338176), is predicted to lead to a loss of Mlh1 protein function. | |
| R498Efs*5 | frameshift | loss of function - predicted | MLH1 R498Efs*5 indicates a shift in the reading frame starting at amino acid 498 and terminating five residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). R498Efs*5 results in loss of interaction with Pms2 and Exo1 in a yeast-two-hybrid assay, reduced Pms2 expression in an in vitro assay (PMID: 12810663), and due to loss of the C-terminal domain (PMID: 16338176), is predicted to lead to a loss of Mlh1 protein function. | |
| R522Gfs*13 | frameshift | loss of function - predicted | MLH1 R522Gfs*13 indicates a shift in the reading frame starting at amino acid 522 and terminating 13 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), R522Gfs*13 is predicted to lead to a loss of Mlh1 protein function. | |
| R522W | missense | unknown | MLH1 R522W lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R522W results in intermediate protein expression compared to wild-type in culture but demonstrates mismatch repair activity similar to wild-type in an in vitro assay (PMID: 23403630), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| R575G | missense | unknown | MLH1 R575G lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R575G has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Dec 2023). | |
| R575K | missense | no effect - predicted | MLH1 R575K lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R575K results in protein expression comparable to wild-type in culture and mismatch repair activity comparable to wild-type in an in vitro assay (PMID: 29520894), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| R659* | nonsense | loss of function - predicted | MLH1 R659* results in a premature truncation of the Mlh1 protein at amino acid 659 of 756 (UniProt.org). R659* results in loss of interaction with Pms2 and Exo1 in a yeast two-hybrid assay (PMID: 12810663), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| R659L | missense | loss of function | MLH1 R659L lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R659L confers a loss of function to the Mlh1 protein as demonstrated by decreased MLH1 gene expression and a reduction in dimerization with Pms2 (PMID: 20533529). | |
| R659P | missense | loss of function | MLH1 R659P lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R659P confers a loss of function to the Mlh1 protein as demonstrated by a loss of mismatch repair activity (MMR) in in-vitro assays (PMID: 20020535, PMID: 21120944) and altered subcellular localization as compared to wild-type (PMID: 21120944). | |
| R659Q | missense | no effect | MLH1 R659Q lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R659Q is predicted to be non-pathogenic based on in silico analyses of the Mlh1 protein and has no effect on mismatch repair activity (MMR) in-vitro (PMID: 22753075, PMID: 21120944) and has subcellular localization similar to wild-type (PMID: 21120944). | |
| R687W | missense | unknown | MLH1 R687W lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R687W results in subcellular localization, protein expression in culture, and mismatch repair activity (MMR) similar to wild-type in an in vitro assay in one study (PMID: 21120944), but in another, results in decreased Mlh1 and Pms2 expression and loss of MMR activity in culture (PMID: 36054288), and therefore, its effect on Mlh1 protein function is unknown. | |
| R69K | missense | no effect - predicted | MLH1 R69K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R69K results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| R725C | missense | unknown | MLH1 R725C lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R725C demonstrates binding to Pms2 similar to wild-type Mlh1 in yeast assays (PMID: 22252508), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| R725H | missense | unknown | MLH1 R725H lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R725H results in similar viability and caspase-3/7 levels, but varied levels of ATM/ATR phosphorylation and gH2AX foci induction compared to wild-type Mlh1 (PMID: 28494185), and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| R755S | missense | unknown | MLH1 R755S does not lie within any known functional domains of the Mlh1 protein (UniProt.org). The functional effect of R755S is conflicting as it results in Mlh1 and Pms2 expression similar to wild-type, retains interaction with Pms2 in culture (PMID: 20533529), and leads to mismatch repair (MMR) activity similar to wild-type in yeast assays (PMID: 17510385) but results in reduced MMR activity in in vitro assays (PMID: 17510385, PMID: 20533529). | |
| R755W | missense | loss of function - predicted | MLH1 R755W does not lie within any known functional domains of the Mlh1 protein (UniProt.org). R755W results in Pms2 stabilization similar to wild-type Mlh1 (PMID: 16338176), but increased microsatellite instability in cultured cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| R9Q | missense | unknown | MLH1 R9Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R9Q has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| R9W | missense | unknown | MLH1 R9W lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R9W results in stable expression of Pms2 and Mlh1 and mismatch repair (MMR) activity comparable to wild-type in culture in one study (PMID: 36054288), but in others demonstrates defective MMR activity in a functional screen in cultured mouse cells (PMID: 31784484), intermediate MMR activity in an in vitro assay, and decreased Mlh1 and Pms2 expression in cultured cells (PMID: 22736432), and therefore, its effect on Mlh1 protein function is unknown. | |
| S106R | missense | loss of function - predicted | MLH1 S106R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S106R results in reduced methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| S193P | missense | loss of function - predicted | MLH1 S193P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S193P results in a loss of mismatch repair (MMR) activity in an in vitro assay (PMID: 17510385), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| S247P | missense | loss of function | MLH1 S247P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S247P results in stable Mlh1 and Pms2 expression but confers a loss of function to the Mlh1 protein as demonstrated by reduced mismatch repair activity in culture (PMID: 36054288) and in an in-vitro assay (PMID: 16083711), altered subcellular localization, and reduced protein expression compared to wild-type Mlh1 in culture (PMID: 21120944). | |
| S252* | nonsense | loss of function - predicted | MLH1 S252* results in a premature truncation of the Mlh1 protein at amino acid 252 of 756 (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), S252* is predicted to lead to a loss of Mlh1 protein function. | |
| S271F | missense | unknown | MLH1 S271F lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S271F has been identified in sequencing studies (PMID: 22842228), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| S295G | missense | unknown | MLH1 S295G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S295G results in mismatch repair activity comparable to wild-type in two of three yeast assays and in an in vitro assay (PMID: 17510385), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| S368L | missense | unknown | MLH1 S368L does not lie within any known functional domains of the Mlh1 protein (UniProt.org). S368L has been identified in sequencing studies (PMID: 31391288, PMID: 37273678), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Apr 2023). | |
| S406N | missense | no effect | MLH1 S406N does not lie within any known functional domains of the Mlh1 protein (UniProt.org). S406N is a common polymorphism (PMID: 12810663, PMID: 17510385) and results in binding to Pms2 and Exo1 comparable to wild-type in a yeast two hybrid assay (PMID: 12810663), Mlh1 and Pms2 expression similar to wild-type Mlh1 in culture, mismatch repair activity comparable to wild-type in culture (PMID: 36054288), in yeast assays, and in in vitro assays (PMID: 17510385, PMID: 20020535), a mutation rate similar to wild-type in one of two yeast assays (PMID: 17210669), and microsatellite stability in a patient sample (PMID: 18033691). | |
| S420C | missense | no effect - predicted | MLH1 S420C lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). S420C results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| S44F | missense | loss of function | MLH1 S44F lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S44F results in reduced expression of Pms2 and Mlh1 in culture (PMID: 36054288), decreased mismatch repair (MMR) activity in in vitro assays (PMID: 17510385, PMID: 15475387) and in cell culture (PMID: 31784484, PMID: 36054288), loss of interaction with Pms2 and Exo1 in yeast two-hybrid assays, and loss of repression activity in a yeast reporter assay (PMID: 12810663). | |
| S46I | missense | unknown | MLH1 S46I lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S46I results in decreased interaction with Pms2 in a yeast assay but Pms2 binding comparable to wild-type in cell culture (PMID: 18094436), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| S505Vfs*3 | frameshift | loss of function - predicted | MLH1 S505Vfs*3 indicates a shift in the reading frame starting at amino acid 505 and terminating 3 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), S505Vfs*3 is predicted to lead to a loss of Mlh1 protein function. | |
| S508N | missense | unknown | MLH1 S508N lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). S508N has been identified in sequencing studies (PMID: 22980975), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2024). | |
| S556N | missense | unknown | MLH1 S556N lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). S556N results in altered splicing (PMID: 15300854), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| S627T | missense | no effect - predicted | MLH1 S627T lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). S627T demonstrates alternative splicing but leads to Mlh1 and Pms2 expression comparable to wild-type and mismatch repair activity similar to wild-type in culture (PMID: 36054288), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| S677Rfs*15 | frameshift | loss of function - predicted | MLH1 S677Rfs*15 indicates a shift in the reading frame starting at amino acid 677 and terminating 15 residues downstream causing a premature truncation of the 756 amino acid Mlh1 protein (UniProt.org). Due to the loss of the C-terminal domain (PMID: 16338176), S677Rfs*15 is predicted to lead to a loss of the Mlh1 protein. | |
| S685F | missense | loss of function - predicted | MLH1 S685F lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). S685F results in reduced Mlh1 and Pms2 protein expression levels in a patient sample and in cell culture (PMID: 32076465), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| S692P | missense | unknown | MLH1 S692P lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). S692P results in reduced expression of Mlh1 and Pms2 but mismatch repair activity comparable to wild-type in culture (PMID: 36054288), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| S698L | missense | unknown | MLH1 S698L lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). S698L has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| S93G | missense | no effect | MLH1 S93G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S93G is predicted to be non-pathogenic based on in silico analyses and has mismatch repair activity comparable to wild-type Mlh1 (PMID: 16083711, PMID: 20020535, PMID: 21120944). | |
| T116K | missense | unknown | MLH1 T116K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). T116K demonstrates no splicing defects (PMID: 18561205) and retains methylation sensitivity in culture (PMID: 30998989), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| T117M | missense | loss of function | MLH1 T117M lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). T117M confers a loss of function to the Mlh1 protein as demonstrated by reduced Pms2 and Mlh1 expression and loss of mismatch repair activity in culture (PMID: 36054288) and in in vitro assays (PMID: 20020535, PMID: 17510385) and has reduced protein expression as compared to wild-type Mlh1 (PMID: 17510385). | |
| T117R | missense | loss of function | MLH1 T117R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). T117R results in decreased mismatch repair (MMR) activity in in vitro assays (PMID: 17510385) and in cell culture (PMID: 31784484), loss of interaction with Pms2 and Exo1 in yeast two-hybrid assays, and decreased repression activity in a yeast reporter assay (PMID: 12810663). | |
| T347I | missense | unknown | MLH1 T347I does not lie within any known functional domains of the Mlh1 protein (Uniprot.org). T347I has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| T413I | missense | no effect - predicted | MLH1 T413I lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). T413I results in mismatch repair activity comparable to wild-type in yeast assays and in an in vitro assay (PMID: 17510385), and therefore, is predicted to have no effect on Mlh1 protein function. | |
| T45_I47delinsCF | indel | loss of function | MLH1 T45_I47delinsCF results in a deletion of three amino acids within the ATPase domain of the Mlh1 protein (PMID: 22753075) from aa 45 to aa 47, combined with the insertion of an cysteine (C) and a phenylalanine (F) at the same site. T45_I47delinsCF confers a loss of function on the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in vitro assay, altered subcellular localization, and reduced protein expression as compared to wild-type (PMID: 21120944). | |
| T662P | missense | unknown | MLH1 T662P lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). T662P results in decreased protein expression of Mlh1 (PMID: 23403630, PMID: 20533529) and Pms2 in culture (PMID: 20533529) and loss of mismatch repair (MMR) activity in yeast assays (PMID: 17510385) but demonstrates MMR activity comparable to wild-type in in vitro assays (PMID: 23403630, PMID: 17510385, PMID: 20533529), and therefore, its effect on Mlh1 protein function is unknown. | |
| T81I | missense | unknown | MLH1 T81I lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). T81I has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| T82A | missense | loss of function | MLH1 T82A lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). T82A confers a loss of function to the Mlh1 protein as demonstrated by deficient mismatch repair activity in in vitro assays (PMID: 22736432) and in cultured cells (PMID: 31881334). | |
| T82I | missense | loss of function | MLH1 T82I lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). T82I results in Mlh1 protein expression comparable to wild-type in a patient tumor sample in one study (PMID: 20587412) but reduced protein expression in culture in another study (PMID: 23403630), loss of mismatch repair activity in a yeast assay (PMID: 17510385) and in in vitro assays (PMID: 17510385, PMID: 23403630), and high microsatellite instability despite expression of Mlh1, Pms2, Msh2, and Msh6 comparable to wild-type in patient tumors (PMID: 20587412). | |
| V113D | missense | loss of function - predicted | MLH1 V113D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V113D results in decreased mismatch repair (MMR) activity in cultured cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| V16L | missense | unknown | MLH1 V16L lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V16L has been identified in the scientific literature (PMID: 32206572, PMID: 34959239), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Dec 2023). | |
| V179D | missense | unknown | MLH1 V179D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V179D retains methylation sensitivity in culture (PMID: 30998989), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| V180G | missense | loss of function - predicted | MLH1 V180G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V180G results in defective mismatch repair (MMR) activity in a functional screen in cultured mouse cells (PMID: 31784484), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| V185G | missense | loss of function | MLH1 V185G lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V185G confers a loss of function on the Mlh1 protein as demonstrated by reduced mismatch repair activity (MMR) in an in-vitro assay, altered subcellular localization, and reduced protein expression as compared to wild-type (PMID: 21120944). | |
| V194I | missense | unknown | MLH1 V194I lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V194I has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| V213M | missense | no effect | MLH1 V213M lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V213M results in decreased Mlh1 and Pms2 expression but demonstrates functional mismatch repair activity in culture (PMID: 36054288) and in in vitro assays, and functional Pms2 interaction in in vitro assays (PMID: 17510385, PMID: 16083711, PMID: 21120944). | |
| V326A | missense | unknown | MLH1 V326A lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). The functional effect of V326A is conflicting as it results in repression activity similar to wild-type Mlh1 in a yeast reporter assay, interaction with Pms2 similar to wild-type Mlh1 in a yeast two-hybrid assay, and mismatch repair (MMR) similar to wild-type in one study (PMID: 11781295), but results in decreased Exo1 interaction in a yeast two-hybrid assay, decreased Pms2 binding in an in vitro assay (PMID: 12810663), and decreased MMR activity in an in vitro assay in another study (PMID: 17510385), and therefore, its effect on Mlh1 protein function is unknown. | |
| V384D | missense | loss of function | MLH1 V384D does not lie within any known functional domains of the Mlh1 protein (UniProt.org). V384D confers a loss of function to Mlh1, as indicated by decreased binding to Pms2 (PMID: 27173243, PMID: 18094436) and reduced MMR activity in in vitro assays (PMID: 17510385). | |
| V440M | missense | unknown | MLH1 V440M lies within the EXO-interacting region of the Mlh1 protein (UniProt.org). V440M has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| V4A | missense | unknown | MLH1 V4A lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V4A has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2023). | |
| V506A | missense | unknown | MLH1 V506A lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). V506A results in reduced binding to Pms2 in an in vitro assay (PMID: 10037723, PMID: 11292842) and reduced binding to Pms2 and Exo1 in a yeast two-hybrid assay (PMID: 12810663), but demonstrates DNA damage response signaling and DNA repair activity similar to wild-type Mlh1 in cultured cells (PMID: 36054288), and therefore, its effect on Mlh1 protein function is unknown. | |
| V612del | deletion | loss of function - predicted | MLH1 V612del results in the deletion of an amino acid within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein at amino acid 612 (PMID: 22753075). V612del results in altered subcellular localization and reduced protein expression compared to wild-type Mlh1 (PMID: 21120944), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| V716M | missense | no effect | MLH1 V716M lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). V716M demonstrates reduced Pms2 and Mlh1 expression in culture but has functional mismatch repair activity in culture (PMID: 36054288) and in in vitro analyses, is predicted to be non-pathogenic based on in silico analyses (PMID: 22753075, PMID: 20020535, PMID: 31881334), and results in subcellular localization and protein expression comparable to wild-type (PMID: 21120944). | |
| W666R | missense | loss of function - predicted | MLH1 W666R lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). W666R demonstrates no splicing defects (PMID: 18561205) but results in reduced methylation sensitivity in culture (PMID: 30998989), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| W712* | nonsense | loss of function - predicted | MLH1 W712* results in a premature truncation of the Mlh1 protein at amino acid 712 of 756 (UniProt.org). W712* results in loss of interaction with Pms2 and Exo1 in a yeast-two-hybrid assay, reduced Pms2 expression in an in vitro assay (PMID: 12810663), and due to loss of the C-terminal domain (PMID: 16338176), is predicted to lead to a loss of Mlh1 protein function. | |
| W714* | nonsense | loss of function - predicted | MLH1 W714* results in a premature truncation of the Mlh1 protein at amino acid 714 of 756 (UniProt.org). W714* results in loss of interaction with Pms2 and Exo1 in a yeast two hybrid assay (PMID: 12810663), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| Y126N | missense | unknown | MLH1 Y126N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). Y126N demonstrates no splicing defects (PMID: 18561205) but results in reduced methylation sensitivity compared to wild-type Mlh1 in culture (PMID: 30998989), altered Mlh1 expression, and microsatellite instability in a patient tumor sample (PMID: 24383517), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| Y379C | missense | unknown | MLH1 Y379C does not lie within any known functional domains of the Mlh1 protein (UniProt.org). Y379C results in splicing similar to wild-type Mlh1 and proficient mismatch repair activity similar to wild-type Mlh1 in an in vitro assay (PMID: 32849802), but has not been fully biochemically characterized and therefore, its effect on Mlh1 protein function is unknown. | |
| Y646C | missense | unknown | MLH1 Y646C lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). Y646C has mismatch repair (MMR) activity comparable to wild-type Mlh1 in in vitro assays (PMID: 16083711, PMID: 21120944), but loss of interaction with Pms2 in cultured cells (PMID: 16724012), and therefore, its effect on Mlh1 protein function is unknown. | |
| Y750* | nonsense | loss of function - predicted | MLH1 Y750* results in a premature truncation of the Mlh1 protein at amino acid 750 of 756 (UniProt.org). Y750* demonstrates expression levels similar to wild-type Mlh1 (PMID: 20533529) but results in a loss of the C-terminal domain, demonstrates decreased stability of the Mlh1/Pms2 heterodimer (PMID: 16338176), leads to reduced Pms2 expression in culture, and reduced mismatch repair activity in an in vitro assay (PMID: 20533529), and therefore, is predicted to lead to a loss of Mlh1 protein function. | |
| Y97D | missense | loss of function - predicted | MLH1 Y97D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). Y97D results in protein expression comparable to wild-type in culture but decreased mismatch repair activity in an in vitro assay (PMID: 29520894), and therefore, is predicted to lead to a loss of Mlh1 protein function. |
CKB BOOST