Pathogenic variants (disease-causing) in the PMS2 gene cause Lynch syndrome (previously known as hereditary non-polyposis colorectal cancer (HNPCC)). People with pathogenic variants in PMS2 have an elevated lifetime risk for primarily colorectal cancer and endometrial (uterine) cancer in women. Individuals may also have increased risks for other Lynch syndrome-associated cancers, including ovarian, gastrointestinal tumors (stomach, small bowel, pancreas), urinary tract (kidney, ureter, bladder), prostate, skin (sebaceous [oil gland] tumors), and brain cancer. Management of PMS2–related tumor risk includes regular surveillance tailored to guidelines to detect tumors early as well as risk-reducing strategies (surgery and medication). PMS2 variants are known to be more common in the Ashkenazi Jewish population.
Pathogenic variants in PMS2 exhibit autosomal dominant inheritance. This means there is a 50% chance the condition can be passed from generation-to-generation. First degree relatives (parents, siblings, children) have a 50% chance to have the same pathogenic variant whereas second degree relatives (grandparents, aunts/uncles, nieces/nephews, half-siblings) have a 25% chance. More distant relatives have lower chances of having the same pathogenic variant when one is identified in the family.
In addition, when an individual inherits pathogenic variants in both copies of the PMS2 gene, it can cause a rare childhood-onset condition called constitutional mismatch repair deficiency (CMMRD). CMMRD results in a risk of childhood onset cancers including colon cancer and leukemia as well as features of a genetic condition called neurofibromatosis type 1 which causes benign skin tumors. CMMRD exhibits autosomal recessive inheritance. This means that both parents must have a single pathogenic variant in the PMS2 gene to have a 25% chance to have a child with the condition.
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Written December 2025
