Pathogenic variants in POLE cause polymerase-proofreading–associated polyposis (PPAP), a hereditary cancer predisposition syndrome characterized by an increased risk for colorectal adenomas (precancerous polyps), early-onset colorectal cancer, and, in some individuals, endometrial cancer. Current management focuses on early and proactive cancer surveillance, including colonoscopy beginning earlier and occurring more frequently than in the general population, as well as individualized risk-based screening for associated cancers. PPAP is not known to be more common in the Ashkenazi Jewish population.
PPAP is caused by pathogenic (disease-causing) variants in the POLE gene and exhibits 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.
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Written December 2025
