MSH2 is a tumor suppressor gene that encodes a key protein in the DNA mismatch repair system, which finds and fixes errors made during DNA replication. The MSH2 protein pairs with MSH6 or MSH3 to form complexes that recognize mismatched base pairs and trigger their repair. Inherited mutations in MSH2 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), predisposing to colorectal, endometrial, ovarian, and other cancers, and biallelic mutations cause constitutional mismatch repair deficiency. Loss of MSH2 function increases the mutation rate and drives tumor development, particularly in colorectal and endometrial cancers, and mismatch-repair-deficient tumors respond particularly well to immune checkpoint inhibitor therapies.

This frameshift is predicted to destroy MSH2 function, the mechanism behind Lynch syndrome, yet it remains a VUS because no clinical evidence (tumor testing, family history, or functional assays) confirms its effect in people. If future studies confirm MSH2 loss, this variant would be expected to confer Lynch syndrome cancer risks, particularly colorectal and endometrial.