MSH6 encodes a protein in the DNA mismatch repair system, which fixes errors made during DNA replication. Partnering with MSH2, it forms a complex that recognizes and helps correct mismatched DNA bases, keeping the genetic code stable. Inherited mutations in MSH6 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), raising the risk of colorectal, endometrial, ovarian, and other cancers, while mutations in both copies lead to constitutional mismatch repair deficiency. Because faulty mismatch repair drives tumor development and produces microsatellite instability, MSH6 acts as a tumor suppressor, and cancers with such repair defects often respond well to immune checkpoint inhibitor therapy.

MSH6 variants are associated with Lynch syndrome and elevated colorectal, endometrial, and ovarian cancer risk, so a pathogenic classification would directly inform cancer screening. This variant, however, remains a variant of uncertain significance: extreme rarity and a moderate computational pathogenicity signal are not enough to confirm or exclude Lynch syndrome, so it should not yet guide clinical decisions.