POLE encodes the catalytic subunit of DNA polymerase epsilon, the enzyme that replicates the leading strand of DNA during cell division and participates in DNA repair. It contains a proofreading domain that corrects replication errors, keeping the accumulation of mutations in check. Germline mutations in POLE cause polyposis and predispose to colorectal cancer, and are also linked to a rare syndrome of facial dysmorphism, immunodeficiency, livedo, and short stature. Somatic mutations, particularly in the proofreading domain, occur in colorectal and endometrial cancers, where they drive an ultra-mutated tumor phenotype and are associated with better responses to immune checkpoint inhibitors.

POLE germline mutations cause polyposis and predispose to colorectal cancer, typically via missense changes in the proofreading exonuclease domain. This intronic variant lies outside that domain, is predicted to have no effect on splicing (SpliceAI max delta 0.06), and is extremely rare in the population, so the finding remains of uncertain significance until functional or familial evidence becomes available.