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 variants predispose to polyposis and colorectal cancer, with pathogenic missense changes concentrated in the exonuclease proofreading domain. This intronic variant is absent from population databases but predicted to have no splice impact, so no evidence links it to POLE disease mechanisms; it remains a variant of uncertain significance pending functional splicing and clinical data.