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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

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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
NM_001258271.1 chr3:g.37050486_37050578del93 c.1897_1989del93 p.S633_K663del31 RefSeq GRCh38/hg38
XM_005265161.2 chr3:g.37050486_37050578del93 c.1897_1989del93 p.S633_K663del31 RefSeq GRCh38/hg38
NM_001354628.2 chr3:g.37048904_37048996del93 c.1897_1989del93 p.V633_E663del31 RefSeq GRCh38/hg38
NM_001258271 chr3:g.37050486_37050578del93 c.1897_1989del93 p.S633_K663del31 RefSeq GRCh38/hg38
NM_000249 chr3:g.37048518_37048610del93 c.1898_1989+1del93 p.E633_E663del31 RefSeq GRCh38/hg38
XM_005265161 chr3:g.37050486_37050578del93 c.1897_1989del93 p.S633_K663del31 RefSeq GRCh38/hg38
NM_001354630.2 chr3:g.37048977_37050537del1561 c.1898_1990del1561 p.K633_H663del31 RefSeq GRCh38/hg38
XM_005265161.3 chr3:g.37050486_37050578del93 c.1897_1989del93 p.S633_K663del31 RefSeq GRCh38/hg38
NM_001354628.1 chr3:g.37048904_37048996del93 c.1897_1989del93 p.V633_E663del31 RefSeq GRCh38/hg38
NM_000249.4 chr3:g.37048518_37048610del93 c.1898_1989+1del93 p.E633_E663del31 RefSeq GRCh38/hg38
NM_000249.3 chr3:g.37048518_37048610del93 c.1898_1989+1del93 p.E633_E663del31 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_001354630.1 chr3:g.37048977_37050537del1561 c.1898_1990del1561 p.K633_H663del31 RefSeq GRCh38/hg38
NM_001354629.1 chr3:g.37048910_37049002del93 c.1897_1989del93 p.W633_T663del31 RefSeq GRCh38/hg38
NM_001258271.2 chr3:g.37050486_37050578del93 c.1897_1989del93 p.S633_K663del31 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 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 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 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 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 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...