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Gene | MLH1 |
Variant | E633_E663del |
Impact List | deletion |
Protein Effect | loss of function |
Gene Variant Descriptions | 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). |
Associated Drug Resistance | |
Category Variants Paths |
MLH1 mutant MLH1 inact mut MLH1 E633_E663del |
Transcript | NM_000249.4 |
gDNA | chr3:g.37048518_37048610del93 |
cDNA | c.1898_1989+1del93 |
Protein | p.E633_E663del31 |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
XM_005265161.2 | chr3:g.37050486_37050578del93 | c.1897_1989del93 | p.S633_K663del31 | RefSeq | GRCh38/hg38 |
NM_000249.4 | chr3:g.37048518_37048610del93 | c.1898_1989+1del93 | p.E633_E663del31 | RefSeq | GRCh38/hg38 |
XM_005265161.3 | chr3:g.37050486_37050578del93 | c.1897_1989del93 | p.S633_K663del31 | RefSeq | GRCh38/hg38 |
NM_001258271 | chr3:g.37050486_37050578del93 | c.1897_1989del93 | p.S633_K663del31 | RefSeq | GRCh38/hg38 |
NM_001354630.1 | chr3:g.37048977_37050537del1561 | c.1898_1990del1561 | p.K633_H663del31 | RefSeq | GRCh38/hg38 |
NM_000249.3 | chr3:g.37048518_37048610del93 | c.1898_1989+1del93 | p.E633_E663del31 | RefSeq | GRCh38/hg38 |
NM_001354630.2 | chr3:g.37048977_37050537del1561 | c.1898_1990del1561 | p.K633_H663del31 | RefSeq | GRCh38/hg38 |
NM_001354628.2 | chr3:g.37048904_37048996del93 | c.1897_1989del93 | p.V633_E663del31 | RefSeq | GRCh38/hg38 |
NM_001258271.2 | chr3:g.37050486_37050578del93 | c.1897_1989del93 | p.S633_K663del31 | RefSeq | GRCh38/hg38 |
NM_001354629.1 | chr3:g.37048910_37049002del93 | c.1897_1989del93 | p.W633_T663del31 | RefSeq | GRCh38/hg38 |
XM_047448152.1 | chr3:g.37048910_37049002del93 | c.1897_1989del93 | p.W633_T663del31 | RefSeq | GRCh38/hg38 |
NM_001354629.2 | chr3:g.37048910_37049002del93 | c.1897_1989del93 | p.W633_T663del31 | RefSeq | GRCh38/hg38 |
NM_001354628.1 | chr3:g.37048904_37048996del93 | c.1897_1989del93 | p.V633_E663del31 | RefSeq | GRCh38/hg38 |
NM_000249 | chr3:g.37048518_37048610del93 | c.1898_1989+1del93 | p.E633_E663del31 | RefSeq | GRCh38/hg38 |
NM_001258271.1 | chr3:g.37050486_37050578del93 | c.1897_1989del93 | p.S633_K663del31 | RefSeq | GRCh38/hg38 |
XM_005265161 | chr3:g.37050486_37050578del93 | c.1897_1989del93 | p.S633_K663del31 | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
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 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 | 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 | 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 | 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 | 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 | 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 | 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... |