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MLH1 S247P - Gene Variant Detail

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Gene MLH1
Variant S247P
Impact List missense
Protein Effect loss of function
Gene Variant Descriptions MLH1 S247P lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). S247P results in stable Mlh1 and Pms2 expression but confers a loss of function to the Mlh1 protein as demonstrated by reduced mismatch repair activity in culture (PMID: 36054288) and in an in vitro assay (PMID: 16083711), altered subcellular localization, and reduced protein expression compared to wild-type Mlh1 in culture (PMID: 21120944).
Associated Drug Resistance
Category Variants Paths

MLH1 mutant MLH1 inact mut MLH1 S247P

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Transcript NM_000249.4
gDNA chr3:g.37014493T>C
cDNA c.739T>C
Protein p.S247P
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_001258271.2 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_000249.3 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_000249 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_001354628.2 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_001258271.1 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_001354630.1 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_001354630.2 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_001258271 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_001354628.1 chr3:g.37014493T>C c.739T>C p.S247P RefSeq GRCh38/hg38
NM_000249.4 chr3:g.37014493T>C c.739T>C p.S247P 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 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 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 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 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 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 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 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...