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 encodes the catalytic subunit of DNA polymerase epsilon, and germline loss-of-function mutations in it cause polyposis and predispose to colorectal cancer. This frameshift, predicted to trigger nonsense-mediated decay and to remove the C-terminal domains needed for holoenzyme assembly, would eliminate this essential replication and repair function, consistent with the gene's established loss-of-function disease mechanism and supporting a Likely Pathogenic classification.