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 pathogenic variants act mainly through exonuclease/proofreading-domain missense hotspots that cause polymerase proofreading-associated polyposis, whereas this change is deep-intronic, leaves the protein product unchanged (NP_006222.2:p.?), and has no supporting functional or segregation data, so its contribution to POLE-associated colorectal cancer predisposition remains unestablished.