MSH6 – Breast Cancer

MSH6 is a core component of the DNA mismatch repair (MMR) pathway, forming the MutSα heterodimer with MSH2 to recognize base–base and single-nucleotide insertion–deletion mismatches. Germline heterozygous pathogenic variants in MSH6 cause Lynch syndrome, characterized by increased colorectal and endometrial cancer risks. Breast cancer has not traditionally been considered part of the Lynch tumor spectrum, but emerging data indicate that MSH6 heterozygosity may also predispose to breast cancer. Accurate classification of MSH6 in breast cancer risk is critical for genetic counseling, diagnostic panels, and personalized management. We reviewed genetic association studies, familial risk estimates, founder analyses, and mechanistic data to assess the clinical validity of the MSH6–breast cancer link.

In a targeted Next-Generation Sequencing (NGS) case-control analysis of MMR genes in 711 hereditary breast cancer (BC) patients, the MSH6 c.3217C>T (p.Pro1073Ser) variant was identified in 26 of 711 (3.7%) patients versus 2 of 492 (0.4%) healthy donors (p = 0.00013, OR = 8.9) (PMID:32547938). Of 32 pathogenic MMR variants detected, the MSH6 variant accounted for 3.6% of hereditary BC cases, indicating significant enrichment compared to controls. Variant classification followed ACMG guidelines, and rarity in population databases supports pathogenicity.

A multicohort study of multiple primary breast cancer (MP-BC) patients showed pathogenic MSH6 variants in 8.5% of MP-BC versus 4.9% of single BC (P = .02) and 7.1% versus 4.2% in an independent cohort (P = .03) (PMID:32954205). TP53 and MSH6 mutations were notably enriched, with younger age at first BC associated with higher MSH6 mutation rates. Comparison to ExAC controls yielded a relative risk >1.6, reaching the genetic evidence cap in multigene panel analyses.

A study of 1,016 Ashkenazi Jewish BC and HBOC patients assessed two recurrent MSH6 founder mutations, c.3984_3987dupGTCA (p.Leu1330ValfsTer12) and c.3959_3962delCAAG (p.Ala1320Thr), detecting five carriers (0.49%) (PMID:30498870). Among cases with personal or first-degree LS-related cancer history (n = 429), 4/429 (0.93%) carried c.3984_3987dup versus 1/587 (0.17%) without such history (p < 0.01), indicating a modest founder effect and supporting population-specific screening.

In a retrospective review of 423 women with LS pathogenic variants, 140 MSH6 carriers had an age-standardized BC SIR of 2.11 (95% CI, 1.56–2.86), confirming a twofold elevated risk (P < 0.001) (PMID:29345684). No significant BC association was observed for MLH1 or MSH2 carriers. BC occurred across diverse ages and histologic subtypes. Large sample size and robust epidemiologic methods lend high confidence to this risk estimate.

Functional assays show that the PWWP domain of MSH6 binds double-stranded DNA, and the S144I mutation impairs domain stability and DNA affinity (PMID:18484749). MSH6-deficient cancer cell lines exhibit 50–750-fold increased mutation rates at the hprt locus, confirming loss of repair fidelity (PMID:9054582). Yeast and mammalian models demonstrate that pathogenic MSH6 mutations disrupt MutSα–PCNA interactions and mismatch recognition, consistent with haploinsufficiency.

Integration of genetic, epidemiologic, founder, and mechanistic data supports a Moderate ClinGen classification for the MSH6–breast cancer association. Although multiple independent proband series and an elevated SIR demonstrate clinical validity, genetic evidence has not yet reached the Strong cap and segregation data remain limited. Functional concordance underpins a loss-of-function mechanism. Current evidence justifies inclusion of MSH6 in hereditary BC testing panels and risk assessment, particularly in LS families. Key Take-home: heterozygous MSH6 pathogenic variants confer a moderate increase in breast cancer risk and should inform genetic counseling and clinical management.

References

• Genetics in medicine • 2018 • MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. PMID:29345684
• Frontiers in oncology • 2020 • Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants. PMID:32547938
• JCO precision oncology • 2020 • Mutation Rates in Cancer Susceptibility Genes in Patients With Breast Cancer With Multiple Primary Cancers. PMID:32954205
• Cancer causes & control • 2019 • The rate of the recurrent MSH6 mutations in Ashkenazi Jewish breast cancer patients. PMID:30498870
• Biochemistry • 2008 • Human mismatch repair protein MSH6 contains a PWWP domain that targets double stranded DNA. PMID:18484749

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