PMS2 is a core component of the post-replicative DNA mismatch repair (MMR) system that heterodimerizes with MLH1 to form MutLα 12. Upon MutSα or MutSβ recognition of DNA mismatches, MutLα is recruited to facilitate assembly of the ternary complex with RFC and PCNA, which activates PMS2's endonuclease activity to introduce strand breaks near mismatches 2. This enables exonuclease EXO1 to degrade the error-containing strand, with PMS2 also recruiting DNA polymerase III for resynthesis 2. PMS2 possesses ATPase activity, though ATP hydrolysis may not be essential for proficient repair 2. The protein also participates in DNA damage signaling, triggering cell cycle arrest or apoptosis upon major damage 2. Heterozygous PMS2 mutations cause Lynch syndrome (LS), responsible for approximately 5-15% of cases, with lower penetrance than other MMR genes 34. Patients carrying pathogenic PMS2 variants show 5.2-fold increased colorectal cancer risk and 7.5-fold increased endometrial cancer risk compared to the general population, with cumulative risks to age 70 of 15-20% and 15% respectively 4. Notably, PMS2 mutations present atypically, with carriers often failing to meet standard Amsterdam criteria 3, and some presenting with breast cancer phenotypes 5. Biallelic mutations cause constitutional mismatch repair deficiency syndrome in childhood 6. Tumor analysis showing isolated PMS2 loss by immunohistochemistry confirms carrier status 3.