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Gene MLH1
Variant V384D
Impact List missense
Protein Effect loss of function
Gene Variant Descriptions MLH1 V384D does not lie within any known functional domains of the Mlh1 protein (UniProt.org). V384D confers a loss of function to Mlh1, as indicated by decreased binding to Pms2 (PMID: 27173243, PMID: 18094436) and reduced MMR activity in in vitro assays (PMID: 17510385).
Associated Drug Resistance
Category Variants Paths

MLH1 mutant MLH1 inact mut MLH1 V384D

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Transcript NM_000249.4
gDNA chr3:g.37025749T>A
cDNA c.1151T>A
Protein p.V384D
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_000249.4 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001354630.2 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001258271.1 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001354620.2 chr3:g.37028819_37028820delTGinsAC c.1151_1152delTGinsAC p.V384D RefSeq GRCh38/hg38
NM_001167617.2 chr3:g.37028819_37028820delTGinsAC c.1151_1152delTGinsAC p.V384D RefSeq GRCh38/hg38
NM_001354628.2 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001258271.2 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001354630.1 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001258271 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001167617.3 chr3:g.37028819_37028820delTGinsAC c.1151_1152delTGinsAC p.V384D RefSeq GRCh38/hg38
NM_001354628.1 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001354620.1 chr3:g.37028819_37028820delTGinsAC c.1151_1152delTGinsAC p.V384D RefSeq GRCh38/hg38
NM_000249 chr3:g.37025749T>A c.1151T>A p.V384D RefSeq GRCh38/hg38
NM_001167617 chr3:g.37028819_37028820delTGinsAC c.1151_1152delTGinsAC p.V384D RefSeq GRCh38/hg38
NM_000249.3 chr3:g.37025749T>A c.1151T>A p.V384D 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 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 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 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 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 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 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 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...