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Gene MLH1
Variant G244D
Impact List missense
Protein Effect loss of function - predicted
Gene Variant Descriptions 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.
Associated Drug Resistance
Category Variants Paths

MLH1 mutant MLH1 inact mut MLH1 G244D

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Transcript NM_000249.4
gDNA chr3:g.37014485G>A
cDNA c.731G>A
Protein p.G244D
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_001354626.1 chr3:g.37047592G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001258271.1 chr3:g.37014485G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354628.1 chr3:g.37014485G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001258271.2 chr3:g.37014485G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_000249.4 chr3:g.37014485G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354628.2 chr3:g.37014485G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354625.2 chr3:g.37047592G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354627.2 chr3:g.37047592G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354627.1 chr3:g.37047592G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354630.1 chr3:g.37014485G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354625.1 chr3:g.37047592G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354626.2 chr3:g.37047592G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354624.2 chr3:g.37047592G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354630.2 chr3:g.37014485G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_001354624.1 chr3:g.37047592G>A c.731G>A p.G244D RefSeq GRCh38/hg38
NM_000249.3 chr3:g.37014485G>A c.731G>A p.G244D RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 inact mut prostate cancer sensitive Enzalutamide + Talazoparib FDA approved Actionable In a Phase III trial (TALAPRO-2) that supported FDA approval, Talzenna (talazoparib) plus Xtandi (enzalutamide) improved median radiographic progression-free survival compared to enzalutamide plus placebo (27.9 vs 16.4 mo, HR 0.46, p=0.0003) in patients with metastatic castration-resistant prostate cancer harboring deficient homologous recombination repair genes including MLH1, with an HR of 0.66 (p=0.12) in patients with non-BRCA mutations treated with Talzenna (talazoparib) (PMID: 37285865; NCT03395197). 37285865 detail...
MLH1 inact mut prostate cancer sensitive Enzalutamide + Talazoparib Guideline Actionable Talzenna (talazoparib) plus Xtandi (enzalutamide) is included in guidelines as systemic therapy for patients with metastatic castration-resistant prostate cancer harboring a pathogenic germline or somatic MLH1 mutation who have not been treated in the setting of castration-resistant prostate cancer (NCCN.org). detail...
MLH1 mutant small intestine adenocarcinoma not applicable N/A Guideline Risk Factor Lynch syndrome results from germline mutations in DNA mismatch repair genes including MLH1, MSH2, MSH6, and PMS2, and is associated with increased risk of developing small bowel adenocarcinoma (NCCN.org). detail...
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 colon cancer not applicable N/A Guideline Risk Factor Lynch syndrome results from germline mutations in DNA mismatch repair genes including MLH1, MSH2, MSH6, and PMS2, and is associated with increased risk of developing colon cancer (NCCN.org). detail...
MLH1 mutant endometrial carcinoma not applicable N/A Guideline Risk Factor Germline mutations in MLH1 result in Lynch syndrome, which is associated with increased risk of developing endometrial carcinoma (NCCN.org). detail...
MLH1 mutant ovarian cancer not applicable N/A Guideline Risk Factor Germline mutations in MLH1 result in Lynch syndrome, which is associated with increased risk of ovarian 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 rectum cancer not applicable N/A Guideline Risk Factor Lynch syndrome results from germline mutations in DNA mismatch repair genes including MLH1, MSH2, MSH6, and PMS2, and is associated with increased risk of developing colorectal cancer (NCCN.org). detail...