MSH6 (mutS homolog 6) is a critical component of the post-replicative DNA mismatch repair (MMR) system. It heterodimerizes with MSH2 to form MutS alpha, which recognizes single base mismatches and insertion-deletion loops in DNA [UniProt annotation]. Upon mismatch detection, MutS alpha undergoes an ATP-dependent conformational transition into a sliding clamp that enables diffusion along DNA, facilitating recruitment of the MutL alpha complex to direct downstream repair events including strand discrimination and resynthesis [UniProt annotation]. MSH6 is recruited to chr2 during G1 and early S phase through its PWWP domain's binding of histone H3K36me3, enabling rapid mismatch identification [UniProt annotation]. MSH6 mutations cause Lynch syndrome, characterized by increased cancer susceptibility. However, MSH6 mutations confer significantly lower cancer risks than MLH1 or MSH2 mutations, with colorectal cancer risk by age 70 reaching only 12% (versus 41-48% for MLH1/MSH2) and ovarian cancer risk remaining below 1% 1. MSH6 mutations are notably enriched in endometrial cancer cohorts (3.8% prevalence) compared to hereditary colorectal cancer families (2.6%) 2. Recent multigene panel studies reveal MSH6 mutations are most frequent among MMR gene mutations and are overrepresented in patients presenting with breast cancer phenotypes rather than classical Lynch syndrome presentations 3. Accurate variant classification combines in vitro MMR activity assessment with computational pathogenicity prediction 4, enabling personalized medical management.