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 leading-strand DNA polymerase catalytic subunit and proofreading enzyme, and germline alterations can predispose to polyposis and colorectal cancer through impaired replication fidelity.
VUS: PM2 supporting because the gnomAD v4.1 allele frequency is 5.581014628459454e-06, below 0.0001. VUS: no pathogenic criterion is met for this missense variant. VUS: no benign criterion or benign combination is met.
East Asian 1 / 44,832 |
0.0022% |
Admixed American 1 / 59,776 |
0.0017% |
South Asian 1 / 90,866 |
0.0011% |
European (non-Finnish) 6 / 1,179,258 |
0.00051% |
East Asian 1 / 19,838 |
0.005% |
Admixed American 1 / 35,190 |
0.0028% |
European (non-Finnish) 2 / 128,692 |
0.0016% |
