PMS2

PMS2 is a human gene that encodes a protein of the DNA mismatch repair (MMR) system. The PMS2 protein is a MutL homolog that forms a heterodimer with MLH1, producing the MutLα complex, the major endonuclease involved in repairing base-base mismatches and small insertion–deletion loops in the genome.

In eukaryotic MMR, the MutSα complex (MSH2–MSH6) recognizes a mismatch and recruits MutLα (MLH1–PMS2). MutLα provides endonuclease activity that initiates repair, coordinating with proliferating cell nuclear antigen (PCNA) and other factors. Exonuclease 1 (EXO1) then removes the error-containing strand segment, and DNA polymerase fills the gap before ligation seals the strand.

Clinically, germline variants in PMS2 predispose to Lynch syndrome (hereditary nonpolyposis colorectal cancer). Carriers have an increased risk of colorectal cancer and other cancers such as endometrial cancer, with penetrance generally lower than that associated with mutations in MLH1 or MSH2. Tumors arising from PMS2 deficiency often display microsatellite instability (MSI), though the phenotype can be heterogeneous. In sporadic cancers, PMS2 expression can be reduced by epigenetic silencing or other mechanisms, contributing to MMR deficiency.

Genetically, PMS2 testing can be complicated by the presence of several pseudogenes that resemble the gene, making sequencing and interpretation challenging. Nevertheless, PMS2 analysis is an important component of comprehensive MMR testing for cancer risk assessment and for guiding surveillance and management in affected families.