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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:
Yes, Lynch syndrome (PMID: 34012068)
NCBI Gene ID Chromosome Map Location Canonical Transcript Gene Role
4292 3 3p22.2 NM_000249 Tumor suppressor (PMID: 30606230)

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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 a loss of mismatch repair activity (MMR) in in vitro assays (PMID: 20020535, PMID: 17510385) and in cell culture (PMID: 31784484).
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, Oct 2022).
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).
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, Oct 2022).
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, Oct 2022).
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.
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, Oct 2022).
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.
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 in one study (PMID: 23403630), and 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), 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, Oct 2022).
C233R missense unknown MLH1 C233R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). C233R has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Oct 2022).
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.
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).
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 2023).
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, Dec 2022).
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.
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 2023).
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).
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, Oct 2022).
D737V missense unknown MLH1 D737V lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). D737V has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Oct 2022).
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).
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 sequencing studies (PMID: 27998968), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Oct 2022).
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, Oct 2022).
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.
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.
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 2023).
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).
E578G missense loss of function MLH1 E578G lies within the EXO1-interacting region and C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E578G confers a loss of function on the Mlh1 protein as demonstrated by a loss of mismatch repair activity (MMR) in an in-vitro assay (PMID: 20020535) and loss of interaction with Pms2 (PMID: 11292842).
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.
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, Oct 2022).
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, Oct 2022).
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.
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, Oct 2022).
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 2023).
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 loss of mismatch repair activity (MMR) 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 2023).
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.
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 in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2023).
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 in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2023).
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 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).
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, Oct 2022).
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 similar mismatch repair activity (MMR) in an in vitro assay, similar subcellular localization, and similar protein expression compared to wild-type Mlh1 (PMID: 21120944, PMID: 31881334).
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, Oct 2022).
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).
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 2023).
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 2023).
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.
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.
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, Oct 2022).
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, Oct 2022).
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.
K616del deletion loss of function - predicted MLH1 K616del 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 616 (PMID: 22753075). 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.
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), but has also been reported to have reduced binding to Pms2 (PMID: 10037723), decreased mismatch repair activity in culture (PMID: 31784484), and to cause reduced cell line viability (PMID: 16982745).
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 2023).
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 therefore, its effect on Mlh1 protein function is unknown.
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).
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, Oct 2022).
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).
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.
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 2023).
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.
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 2023).
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 2023).
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.
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, Oct 2022).
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).
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, Dec 2022).
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), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2023).
M587V missense unknown MLH1 M587V lies within 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 2023).
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, Oct 2022).
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.
negative unknown loss of function MLH1 negative indicates a lack of expression of the MLH1 mRNA and/or protein.
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.
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.
P640L missense loss of function - predicted MLH1 P640L lies within 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 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.
P648L missense unknown MLH1 P648L lies within 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 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, Oct 2022).
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, Oct 2022).
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, Oct 2022).
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, Oct 2022).
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 decreased mismatch repair (MMR) activity in an in vitro assay (PMID: 17510385) and in cell culture (PMID: 31784484).
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 in the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). Q689R has no effect on the Mlh1 protein function as demonstrated by functional mismatch repair (MMR) activity in in vitro assays (PMID: 21404117, PMID: 17510385).
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 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), increased Mlh1 degradation, and decreased Pms2 interaction compared to wild-type in cell culture (PMID: 31697235).
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.
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.
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).
R265S missense loss of function - predicted MLH1 R265S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R265S 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.
R325W missense unknown MLH1 R325W lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R325W has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Oct 2022).
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, Oct 2022).
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 not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Oct 2022).
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.
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.
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, Nov 2022).
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 no effect MLH1 R687W lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R687W is predicted to have no effect on the Mlh1 protein as demonstrated by similar mismatch repair activity (MMR) in an in-vitro assay, similar subcellular localization, and similar protein expression as compared to wild-type (PMID: 21120944).
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, Oct 2022).
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 2023).
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, Oct 2022).
R9W missense loss of function - predicted MLH1 R9W lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R9W results in defective mismatch repair (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, 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 confers a loss of function to 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).
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, Oct 2022).
S368L missense unknown MLH1 S368L does not lie within any known functional domains of the Mlh1 protein (UniProt.org). S368L has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Oct 2022).
S44F missense loss of function MLH1 S44F lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S44F results in decreased mismatch repair (MMR) activity in in vitro assays (PMID: 17510385, PMID: 15475387) and in cell culture (PMID: 31784484), loss of interaction with Pms2 and Exo1 in yeast two-hybrid assays, and loss of repression activity in a yeast reporter assay (PMID: 12810663).
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 2023).
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.
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, Oct 2022).
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).
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 loss of mismatch repair (MMR) activity in in vitro assays (PMID: 20020535, PMID: 17510385) and has reduced protein expression as compared to wild-type (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, Oct 2022).
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).
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, Oct 2022).
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).
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 sequencing studies (PMID: 32206572), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2022).
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, Oct 2022).
V213M missense no effect MLH1 V213M lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). V213M demonstrates functional mismatch repair activity and Pms2 interaction in in vitro assays (PMID: 17510385, PMID: 16083711, PMID: 21120944), and thus, has no effect on Mlh1 function.
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, Oct 2022).
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, Oct 2022).
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 is predicted to be non-pathogenic based on in silico analyses, has mismatch repair activity comparable to wild-type Mlh1 (PMID: 22753075, PMID: 20020535, PMID: 31881334), similar subcellular localization, and similar protein expression as compared to wild-type (PMID: 21120944).
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.
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 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 funciton is unknown.