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Gene MLH1
Variant L582V
Impact List missense
Protein Effect loss of function - predicted
Gene Variant Descriptions 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.
Associated Drug Resistance
Category Variants Paths

MLH1 mutant MLH1 inact mut MLH1 L582V

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Transcript NM_000249.4
gDNA chr3:g.37047531C>G
cDNA c.1744C>G
Protein p.L582V
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_001354628.1 chr3:g.37047531C>G c.1744C>G p.L582V RefSeq GRCh38/hg38
NM_001354628.2 chr3:g.37047531C>G c.1744C>G p.L582V RefSeq GRCh38/hg38
XM_047448152.1 chr3:g.37047630C>G c.1744C>G p.L582V RefSeq GRCh38/hg38
NM_001354629.2 chr3:g.37047630C>G c.1744C>G p.L582V RefSeq GRCh38/hg38
NM_001258271.1 chr3:g.37047531C>G c.1744C>G p.L582V RefSeq GRCh38/hg38
NM_000249.4 chr3:g.37047531C>G c.1744C>G p.L582V RefSeq GRCh38/hg38
NM_001258271.2 chr3:g.37047531C>G c.1744C>G p.L582V RefSeq GRCh38/hg38
NM_000249.3 chr3:g.37047531C>G c.1744C>G p.L582V 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 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 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 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 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 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 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 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 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...
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...