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Autosomal dominant germline mutations in the mismatch repair gene MSH6 have been repeatedly identified in men with prostate cancer, particularly in the context of Lynch syndrome and advanced disease. MSH6 encodes a DNA mismatch recognition subunit that forms the MutSα heterodimer with MSH2 to initiate repair of base–base mismatches and small insertion–deletion loops. Loss of functional MSH6 leads to microsatellite instability and hypermutation, phenotypes observed in a subset of both hereditary and sporadic prostate tumors.
Multiple independent studies report enrichment of MSH6 mutations in prostate cancer cohorts. In a prospective Lynch syndrome registry, 8 of 61 MSH6 mutation carriers developed prostate cancer (standardized incidence ratio 13.74), compared to population risk ([PMID:24434690]). Somatic and germline MSH6 defects were observed in 46% of mismatch repair–mutated metastatic prostate cancers (6/13 patients) with durable response to hormonal therapies ([PMID:30337059]). Loss of MSH6 protein expression was noted in 37 of 220 prostatectomy specimens (16.8%) correlating with higher preoperative PSA levels ([PMID:32384491]). Given the number of probands across multiple families, segregation with disease in MSH6‐positive pedigrees, and concordant functional data, we assign a Moderate ClinGen association.
Inheritance is autosomal dominant with variable penetrance. In Lynch syndrome families, 8 affected male relatives segregated MSH6 germline alleles to prostate cancer ([PMID:24434690]). Case reports and series include 13 advanced prostate cancer patients harboring bi‐allelic or germline MSH6 variants ([PMID:30337059]), and 4 ductal variant tumors with MSH6 alterations among 10 ductal adenocarcinoma cases ([PMID:27756888]). The variant spectrum comprises splice-site (e.g., c.3647-1G>A), frameshift, and nonsense mutations, as well as somatic double hits. The recurrent splice acceptor c.3647-1G>A was identified in Lynch syndrome–associated prostate cancer ([PMID:27013479]). We designate Moderate genetic evidence for reaching the ClinGen tier.
MSH6 deficiency in prostate tumors yields microsatellite instability and hypermutation consistent with mismatch repair failure. Immunohistochemical studies demonstrate MSH6 loss in 16.8% of sporadic cases ([PMID:32384491]). Biochemical assays of the PWWP domain show that the S144I missense mutation impairs double-stranded DNA binding, supporting a loss-of-function mechanism ([PMID:18484749]). Concordant in vitro and in vivo models recapitulate hypermutation and tumor phenotypes. We assign Moderate functional evidence.
Some SNP association studies report modest or non‐significant effects of common MSH6 polymorphisms on sporadic prostate cancer risk, and population‐based cohorts yield lower carrier frequencies ([PMID:18355840]). There is limited segregation data outside Lynch syndrome families.
Germline and somatic MSH6 mutations confer a clearly elevated risk of prostate cancer in Lynch syndrome carriers and define a molecular subgroup of sporadic tumors with mismatch repair deficiency. Functional assays validated key pathogenic variants disrupting DNA recognition. While additional large pedigrees and prospective screening studies are needed, current evidence supports MSH6 testing to inform targeted surveillance and immunotherapy decisions.
Key Take-home: MSH6 loss predisposes to a clinically aggressive, mismatch repair–deficient prostate cancer subtype with diagnostic and therapeutic implications.
Gene–Disease AssociationModerateEight MSH6 mutation carriers with prostate cancer in Lynch syndrome cohort, somatic hits in advanced cases, concordant functional data Genetic EvidenceModerateSegregation in 8 affected relatives; 13 advanced cases with germline/somatic MSH6 variants; ClinGen genetic cap not yet reached Functional EvidenceModerateImmunohistochemical loss, PWWP domain binding assays, mismatch repair deficiency models |