Gene Detail

Gene Symbol MLH1
Synonyms COCA2 | FCC2 | hMLH1 | HNPCC | HNPCC2
Gene Description MLH1, MutL protein homolog 1, is a tumor suppressor 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). 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 v2.0:
Yes, Lynch syndrome (PMID: 27854360)
Entrez Id 4292
Chromosome 3
Map Location 3p22.2
Canonical Transcript NM_000249

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Variant Impact Protein Effect Variant Description Associated with drug Resistance
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).
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 dimerization domain (PMID: 22753075), S505Vfs*3 is predicted to lead to a loss of Mlh1 protein function.
Q60P missense unknown MLH1 Q60P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). Q60P results in partial loss of DNA mismatch repair activity in yeast (PMID: 15475387) and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
S677Rfs*15 frameshift unknown 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). S677Rfs*15 has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Jan 2018).
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).
T82A missense loss of function - predicted MLH1 T82A does not lie within any known functional domains of the Mlh1 protein (UniProt.org). T82A may confer a loss of function to the Mlh1 protein as demonstrated by loss of mismatch repair activity in an in-vitro assay (PMID: 22736432).
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).
A120S missense unknown MLH1 A120S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A120S has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
R9Q missense unknown MLH1 R9Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R9Q has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
E460A missense no effect MLH1 E460A lies within the EXO1-interacting region of the Mlh1 protein (UniProt.org). E406A 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).
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).
E319K missense unknown MLH1 E319K lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). E319K has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
R659L missense loss of function MLH1 R659L does not lie within any known functional domains of the Mlh1 protein (UniProt.org). 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).
E37K missense loss of function - predicted MLH1 E37K lies within an ATP binding region in the ATPase domain of the Mlh21 protein (PMID: 22753075). E37K results in a loss of mismatch repair activity (MMR) of the Mlh1 protein in an in-vitro assay (PMID: 20020535).
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, Aug 2018).
P640S missense unknown MLH1 P640S lies within EXO1-interacting region of the Mlh1 protein (PMID: 22753075). P640S has been identified in the scientific literature (PMID: 25871441), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
S368L missense unknown MLH1 S368L lies within EXO1-interacting region of the Mlh1 protein (PMID: 22753075). S368L has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
L550I missense unknown MLH1 L550I lies within the EXO1-interacting region 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, Aug 2018).
P578_E632del deletion loss of function MLH1 P578_E632del results in deletion of 54 amino acids within the EXO1-interacting region of the Mlh1 protein (UniProt.org) from aa 578 to aa 632. 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).
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, Aug 2018).
L658I missense unknown MLH1 L658I lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L658I has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
P403S missense no effect - predicted MLH1 P403S does not lie within any known functional domains of the Mlh1 protein (PMID: 22753075). P403S is predicted to be benign in multiple in silico analyses (PMID: 22753075) and has mismatch repair activity comparable to Mlh1 wild-type in an in-vitro assay (PMID: 20020535).
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, Aug 2018).
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 dimerization domain (PMID: 22753075), F530Lfs*5 is predicted to lead to a loss of Mlh1 protein function.
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, Aug 2018).
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 the Mlh1 protein in an in-vitro assay (PMID: 20020535).
L588R missense unknown MLH1 L588R lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). L588R has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
E703A missense unknown MLH1 E703A lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E703A has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
loss unknown loss of function MLH1 loss indicates loss of the MLH1 gene, mRNA, and protein.
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, Aug 2018).
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, Aug 2018).
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 dimerization domain (PMID: 22753075), R226* 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, Aug 2018).
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, Aug 2018).
S508N missense unknown MLH1 S508N lies within EXO1-interacting region 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, Aug 2018).
R100* nonsense loss of function - predicted MLH1 R100* results in a premature truncation of the Mlh1 protein at amino acid 100 of 756 within the ATPase domain of the Mlh1 protein (UniProt.org, PMID: 22753075). Due to the loss of the majority of the ATPase domain and loss of the C-terminal dimerization domain (PMID: 22753075), R100* is predicted to lead to a loss of Mlh1 protein function.
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).
P648S missense unknown MLH1 P648S lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). The functional effect of P648S is conflicting, as P648S shows mismatch repair (MMR) activity and PMS2 binding similar to wild-type Mlh1 in in-vitro assays (PMID: 20020535, PMID: 16083711, PMID: 15139004), but has also shown decreased PMS2 binding (PMID: 16724012), altered subcellular localization, and reduced protein expression (PMID: 21120944).
R725H missense unknown MLH1 R725H lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). R725H has been identified in the scientific literature (PMID: 25142776), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
G67W missense loss of function - predicted MLH1 G67W lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G67W demonstrates decreased mismatch repair activity (MMR) in an in-vitro assay as compared to wild-type (PMID: 17510385).
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, Aug 2018).
K618E missense unknown MLH1 K618E lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). K618E has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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 not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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), similar subcellular localization, and similar 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 not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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 all domains known to interact with other DNA repair enzymes (PMID: 22753075), E227* is predicted to lead to a loss of 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 dimerization domain (PMID: 22753075), R487* 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 (UniProt.org). A410T has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
L590I missense unknown MLH1 L590I lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). L590I has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
V194I missense unknown MLH1 V194I lies within the protein kinase 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, Aug 2018).
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, Aug 2018).
D41N missense unknown MLH1 D41N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). D41N has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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 an in-vitro assay (PMID: 20020535, PMID: 17510385), altered subcellular localization, and reduced protein expression as compared to wild-type (PMID: 21120944).
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 as compared to wild-type (PMID: 21120944).
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).
K118N missense unknown MLH1 K118N lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). K118N 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, Aug 2018).
N187Y missense unknown MLH1 N187Y lies within the protein kinase domain of the Mlh1 protein (PMID: 22753075). N187Y has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
D631H missense unknown MLH1 D631H lies within the EXO1-interacting region 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, Aug 2018).
A20V missense unknown MLH1 A20V does not lie within any known functional domains of the Mlh1 protein (UniProt.org). A20V does not alter Mlh1 amino acid polarity and is predicted not to be disease causing (PMID: 21901162), however A20V has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
N338S missense unknown MLH1 N338S does not lie within any known functional domains of the Mlh1 protein (UniProt.org). N338S has been identified in sequencing studies (PMID: 24344984), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
R217C missense unknown MLH1 R217C lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). The functional effect of R217C is conflicting, as R217C has been predicted to be non-pathogenic based on in silico analyses (PMID: 17510385, PMID: 17192056) and was found to have mismatch repair activity (MMR) similar to wild-type Mlh1 in a cell based assay (PMID: 11781295), however, R217C has also been reported to have impaired interaction with Pms2 (PMID: 27173243).
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 all domains known to interact with other DNA repair enzymes (PMID: 22753075), E313* is predicted to lead to a loss of Mlh1 protein function.
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).
H329P missense loss of function - predicted MLH1 H329P does not lie within any known functional domains of the Mlh1 protein (UniProt.org). H329P may confer a loss of function on the Mlh1 protein as demonstrated by altered subcellular localization and reduced protein expression as compared to wild-type (PMID: 21120944).
V213M missense no effect MLH1 V213M lies within the ATPase domain of the Mlh1 protein (PIMD: 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.
P640L missense unknown MLH1 P640L lies within EXO1-interacting region of the Mlh1 protein (PMID: 22753075). P640L has been identified in the scientific literature (PMID: 25871441), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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).
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 demonstrated by reduced mismatch repair activity (MMR) in an in-vitro assay (PMID: 16083711, 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, Aug 2018).
Q26R missense unknown MLH1 Q26R does not lie within any known functional domains of the Mlh1 protein (UniProt.org). Q26R has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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).
L622H missense unknown MLH1 L622H lies within the interaction with EXO1 region of the Mlh1 protein (UniProt.org). The functional effect of L622H is conflicting, as L622H has been reported to have decreased gene expression and defects in protein stability (PMID: 23403630), but mismatch repair activity (MMR) similar to wild-type Mlh1 (PMID: 17510385).
G532C missense unknown MLH1 G532C lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). G532A has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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.
R389Q missense no effect - predicted MLH1 R389Q does not lie within any known functional domains of Mlh1 protein (UniProt.org). R389Q is predicted to have no effect on the Mlh1 protein as demonstrated by similar mismatch repair activity (MMR) in an in-vitro assay as compared to wild-type (PMID: 17510385).
I565M missense unknown MLH1 I565M lies within the EXO1-interacting region 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, Aug 2018).
R659* nonsense unknown MLH1 R659* results in a premature truncation of the Mlh1 protein at amino acid 659 of 756 (UniProt.org). R659* has been identified in the scientific literature (PMID: 20167975), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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 all domains known to interact with other DNA repair enzymes (PMID: 22753075), E102* is predicted to lead to a loss of Mlh1 protein function.
K618T missense unknown MLH1 K618T lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). The functional effect of K618T is conflicting, as K618T 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 (PMID: 10037723).
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 dimerization domain (PMID: 22753075), F522Gfs*13 is predicted to lead to a loss of Mlh1 protein function.
H543R missense unknown MLH1 H543R lies within the EXO1-interacting region 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, Aug 2018).
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).
T347I missense unknown MLH1 T347I lies within the protein kinase domain of the Mlh1 protein (PMID: 22753075). T347I has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
E754Q missense unknown MLH1 E754Q does not lie within any known functional domains of the Mlh1 protein (PMID: 22753075). E754Q has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
Q689R missense no effect MLH1 Q689R does not lie within any known functional domains of the Mlh1 protein (UniProt.org). 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).
P648L missense unknown MLH1 P648L lies within EXO1-interacting region of the Mlh1 protein (PMID: 22753075). The functional effect of P648L is conflicting, as P648L shows decreased binding to Exo1 and PMS2 in some assays (PMID: 22753075), altered subcellular localization and reduced protein expression (PMID: 21120944), but normal interaction with PMS2 (PMID: 16083711) and has functional mismatch repair activity (PMID: 20020535, PMID: 16083711).
G357A missense unknown MLH1 G357A does not lie within any known functional domains of the Mlh1 protein (PMID: 22753075). 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, Aug 2018).
N551T missense unknown MLH1 N551T lies within the interaction with EXO1 region of the Mlh1 protein (UniProt.org). The functional effect of N551T is conflicting, as N551T has been reported to have decreased expression compared to wild-type (PMID: 23403630), however in an in-vitro mismatch repair (MMR) assay, N551T had activity similar to wild-type (PMID: 17510385).
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, Aug 2018).
S271F missense unknown MLH1 S271F lies within the protein kinase domain of the Mlh1 protein (PMID: 22753075). S271F has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
A31C missense loss of function - predicted MLH1 A31C lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A31C has reduced mismatch repair activity (MMR) relative to wild-type Mlh1 in an in-vitro assay (PMID: 20020535).
E633_E663del deletion loss of function MLH1 E633_E663del results in deletion of 31 amino acids within the EXO1-interacting region of the Mlh1 protein (UniProt.org) from aa 633 to aa 663. 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).
N38K missense loss of function - predicted MLH1 N38K lies within an ATP binding domain within the ATPase domain of the Mlh1 protein (PMID: 22753075). N38K may confer a loss of function to the Mlh1 protein as demonstrated by a loss of mismatch repair activity in an in-vitro assay (PMID: 20020535).
H109D missense unknown MLH1 H109D lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). H109D has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
K443Q missense no effect MLH1 K443Q lies within the Exo1 interaction domain 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.
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, Aug 2018).
K616del deletion loss of function - predicted MLH1 K616del results in the deletion of an amino acid within the EXO1-interacting region of the Mlh1 protein at amino acid 616 (UniProt.org). K616del may confer a loss of function on the Mlh1 protein as demonstrated by altered subcellular localization and reduced protein expression as compared to wild-type (PMID: 21120944).
I630S missense unknown MLH1 I630S lies within the EXO1-interacting region 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, Aug 2018).
R385C missense unknown MLH1 R385C does not lie within any known functional domains of the Mlh1 protein (PMID: 22753075). R385C has been identified in the scientific literature (PMID: 15222003, PMID: 25115387), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
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 dimerization domain (PMID: 22753075), S252* is predicted to lead to a loss of Mlh1 protein function.
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, Aug 2018).
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, Aug 2018).
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).
V612del deletion loss of function - predicted MLH1 V612del results in the deletion of an amino acid within the EXO1-interacting region of the Mlh1 protein at amino acid 612 (UniProt.org). V612del may confer a loss of function on the Mlh1 protein as demonstrated by altered subcellular localization and reduced protein expression as compared to wild-type (PMID: 21120944).
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).
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 dimerization domain (PMID: 22753075), L507* is predicted to lead to a loss of Mlh1 protein function.
C233R missense unknown MLH1 C233R lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). C233R has not been characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
A589D missense unknown MLH1 A589D lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). The functional effect of A589D is conflicting, as A589D has been reported to result in a loss of mismatch repair activity (PMID: 20020535) and also to have proficient mismatch repair activity (PMID: 16083711) in in-vitro assays, but has altered subcellular localization and reduced protein expression as compared to wild-type (PMID: 21120944).
R265S missense loss of function - predicted MLH1 R265S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R265S may confer a loss of function to the Mlh1 protein as demonstrated by a loss of mismatch repair activity in an in-vitro assay (PMID: 20020535).
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).
K618A missense unknown MLH1 K618A lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). The functional effect of K618A is conflicting, as K618A has 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) and to cause reduced cell line viability (PMID: 16982745).
N38H missense loss of function - predicted MLH1 N38H lies within an ATP binding domain within the ATPase domain of the Mlh1 protein (PMID: 22753075). N38H may confer a loss of function to the Mlh1 protein as demonstrated by a loss of mismatch repair activity in an in-vitro assay (PMID: 20020535).
E578G missense loss of function MLH1 E578G lies within the C-terminal dimerization domain (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).
V16L missense unknown MLH1 V16L lies within the ATPase domain of the Mlh1 protein (PIMD: 22753075). V16L has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
mutant unknown unknown MLH1 mutant indicates an unspecified mutation in the MLH1 gene.
I330del deletion loss of function MLH1 I330del results in the deletion of an amino acid in an unknown region 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).
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).
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, Aug 2018).
G101S missense unknown MLH1 G101S lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). G101S has been identified in sequencing studies (PMID: 24278394), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
V506A missense loss of function MLH1 V506A lies within the interaction with EXO1 region of the Mlh1 protein (UniProt.org). V506A confers a loss of function to the Mlh1 protein as demonstrated by reduced binding to Pms2 when compared to wild-type, in-vitro (PMID: 10037723, PMID: 11292842).
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 all known functional domains (PMID: 22753075), E34* 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 demonstrates decreased mismatch repair activity (MMR) in an in-vitro assay (PMID: 17510385).
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).
V384D missense loss of function - predicted MLH1 V384D does not lie within any known functional domains of the Mlh1 protein (UniProt.org). V384D is a common MLH1 polymorphism (PMID: 25823662) predicted to result in a loss of function as demonstrated by decreased binding to Pms2 (PMID: 27173243, PMID: 18094436) and reduced MMR activity in vitro (PMID: 17510385).
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).
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).
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 A681T has been reported to result in a loss of mismatch repair activity (PMID: 16083711), but has also shown normal mismatch repair activity and similar subcellular localization and protein expression as wild-type (PMID: 21120944).
D737V missense unknown MLH1 D737V lies within close proximity to the heterodimerization S1 site of the Mlh1 protein (PMID: 23435383). D737V has not been biochemically characterized and therefore, the protein effect on MLH1 is unknown, however, D737V has been described as a deleterious mutation as determined by bioinformatic algorithims (PMID: 18383312, PMID: 23435383).
L559R missense loss of function MLH1 L559R lies within the interaction with EXO1 region of the Mlh1 protein (UniProt.org). 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).
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).
L582F missense loss of function - predicted MLH1 L582F lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). L582F results in a loss of mismatch repair activity (MMR) of the Mlh1 protein in an in-vitro assay (PMID: 20020535).
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).
W714* nonsense unknown MLH1 W714* results in a premature truncation of the Mlh1 protein at amino acid 714 of 756 (UniProt.org). W714* 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, Aug 2018).
L550P missense unknown MLH1 L550P lies within the EXO1-interacting region of the Mlh1 protein (PMID: 22753075). The functional effect of L550P is conflicting, as L550P has been reported to have active mismatch repair activity (PMID: 16083711) and also have a loss of mismatch repair activity in an in-vitro assay (PMID: 20020535), but has similar localization and protein expression as wild-type (PMID: 21120944)
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, Aug 2018).
A111P missense loss of function - predicted MLH1 A111P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). A111P results in a loss of mismatch repair activity (MMR) in an in-vitro assay (PMID: 20020535).
M587V missense unknown MLH1 M587V lies within EXO1-interacting region of the Mlh1 protein (UniProt.org). M587V has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
R325W missense unknown MLH1 R325W does not lie within any known functional domains of the Mlh1 protein (UniProt.org). R325W has not been characterized in the scientific literature and therefore, its effect on Mlh1 protein function is unknown (PubMed, Aug 2018).
Y646C missense no effect MLH1 Y646C lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). Y646C is predicted to be non-pathogenic based on in silico analyses and has mismatch repair activity comparable to wild-type Mlh1 in in-vitro assays (PMID: 16083711, PMID: 21120944).
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, Aug 2018).
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, Aug 2018).
Molecular Profile Protein Effect Treatment Approaches
MLH1 A29S no effect
MLH1 S505Vfs*3 loss of function - predicted
MLH1 Q60P unknown
MLH1 S677Rfs*15 unknown
MLH1 T117M loss of function
MLH1 T82A loss of function - predicted
MLH1 D63E loss of function
MLH1 A120S unknown
MLH1 R9Q unknown
MLH1 E460A no effect
MLH1 R265C loss of function
MLH1 E319K unknown
MLH1 R659L loss of function
MLH1 E37K loss of function - predicted
MLH1 Q48E unknown
MLH1 P640S unknown
MLH1 S368L unknown
MLH1 L550I unknown
MLH1 P578_E632del loss of function
MLH1 D41Y unknown
MLH1 L658I unknown
MLH1 P403S no effect - predicted
MLH1 V440M unknown
MLH1 F530Lfs*5 loss of function - predicted
MLH1 I190T unknown
MLH1 H109P loss of function - predicted
MLH1 L588R unknown
MLH1 E703A unknown
MLH1 loss loss of function
MLH1 Q391R unknown
MLH1 S698L unknown
MLH1 R226* loss of function - predicted
MLH1 R487L unknown
MLH1 A92T unknown
MLH1 S508N unknown
MLH1 R100* loss of function - predicted
MLH1 P654L loss of function
MLH1 P648S unknown
MLH1 R725H unknown
MLH1 G67W loss of function - predicted
MLH1 A210T unknown
MLH1 K618E unknown
MLH1 L155P unknown
MLH1 V716M no effect
MLH1 D72Y unknown
MLH1 E227* loss of function - predicted
MLH1 R487* loss of function - predicted
MLH1 A410T unknown
MLH1 L590I unknown
MLH1 V194I unknown
MLH1 K254N unknown
MLH1 D41N unknown
MLH1 G67R loss of function
MLH1 I219V no effect
MLH1 R659P loss of function
MLH1 K118N unknown
MLH1 N187Y unknown
MLH1 D631H unknown
MLH1 A20V unknown
MLH1 N338S unknown
MLH1 R217C unknown
MLH1 E313* loss of function - predicted
MLH1 L155R loss of function
MLH1 H329P loss of function - predicted
MLH1 V213M no effect
MLH1 P640L unknown
MLH1 V185G loss of function
MLH1 F80V loss of function
MLH1 T81I unknown
MLH1 Q26R unknown
MLH1 R659Q no effect
MLH1 L622H unknown
MLH1 G532C unknown
MLH1 inact mut loss of function
MLH1 R389Q no effect - predicted
MLH1 I565M unknown
MLH1 R659* unknown
MLH1 E102* loss of function - predicted
MLH1 K618T unknown
MLH1 R522Gfs*13 loss of function - predicted
MLH1 H543R unknown
MLH1 C77R loss of function
MLH1 T347I unknown
MLH1 E754Q unknown
MLH1 Q689R no effect
MLH1 P648L unknown
MLH1 G357A unknown
MLH1 N551T unknown
MLH1 P709Q unknown
MLH1 S271F unknown
MLH1 A31C loss of function - predicted
MLH1 E633_E663del loss of function
MLH1 N38K loss of function - predicted
MLH1 H109D unknown
MLH1 K443Q no effect
MLH1 K241N unknown
MLH1 K616del loss of function - predicted
MLH1 I630S unknown
MLH1 R385C unknown
MLH1 S252* loss of function - predicted
MLH1 E199K unknown
MLH1 E172K unknown
MLH1 K84E loss of function
MLH1 V612del loss of function - predicted
MLH1 S247P loss of function
MLH1 L507* loss of function - predicted
MLH1 C233R unknown
MLH1 A589D unknown
MLH1 R265S loss of function - predicted
MLH1 E71del loss of function
MLH1 K618A unknown
MLH1 N38H loss of function - predicted
MLH1 E578G loss of function
MLH1 V16L unknown
MLH1 mutant unknown
MLH1 I330del loss of function
MLH1 L749P loss of function
MLH1 V4A unknown
MLH1 G101S unknown
MLH1 V506A loss of function
MLH1 E34* loss of function - predicted
MLH1 E102D loss of function - predicted
MLH1 I107R loss of function
MLH1 V384D loss of function - predicted
MLH1 P28L loss of function
MLH1 T45_I47delinsCF loss of function
MLH1 A681T unknown
MLH1 D737V unknown
MLH1 L559R loss of function
MLH1 R687W no effect
MLH1 L582F loss of function - predicted
MLH1 S93G no effect
MLH1 W714* unknown
MLH1 L550P unknown
MLH1 I262M unknown
MLH1 A111P loss of function - predicted
MLH1 M587V unknown
MLH1 R325W unknown
MLH1 Y646C no effect
MLH1 H315Y unknown
MLH1 R725C unknown
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MLH1 loss colon cancer sensitive KU60648 Preclinical - Cell culture Actionable In a preclinical study, MLH1 deficient colon cancer cell lines were sensitive to KU60648 in culture, demonstrating decreased cell viability and reduced colony formation (PMID: 28224663). 28224663
MLH1 inact mut colorectal cancer not applicable N/A Preclinical Emerging In a preclinical study, MLH1 inactivation through hypermethylation was associated with high microsatellite instability (MSI-H) colorectal carcinoma by whole genome sequencing of tumor samples (PMID: 22810696), suggesting it may be a potential biomarker. 22810696
MLH1 mutant pancreatic cancer not applicable N/A Guideline Risk Factor Germline mutations in MLH1 result in Lynch syndrome, which is associated with increased risk of developing pancreatic cancer (NCCN.org). detail...
MLH1 mutant stomach cancer not applicable N/A Guideline Risk Factor Germline mutations in MLH1 result in Lynch syndrome, which is associated with increased risk of early onset of gastric cancer (NCCN.org). detail...
MLH1 mutant endometrial cancer not applicable N/A Guideline Risk Factor Germline mutations in MLH1 result in Lynch syndrome, which is associated with increased risk of developing endometrial cancer (NCCN.org). detail...