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.
This deep-intronic substitution lies well outside the POLE exonuclease proofreading domain whose defects drive polymerase proofreading-associated polyposis and colorectal cancer predisposition, and it produces no predicted change to splicing or to the polymerase epsilon protein, so its clinical significance in that gene context remains unresolved.
BP4 supporting: the deep-intronic change has SpliceAI max delta 0.003, below the 0.1 no-impact cutoff, so no splice effect is predicted.
African/African American 409 / 72,922 |
0.56% 2 hom |
Remaining individuals 27 / 59,450 |
0.045% |
Admixed American 21 / 51,582 |
0.041% |
Middle Eastern 1 / 4,932 |
0.02% |
South Asian 4 / 80,016 |
0.005% |
European (non-Finnish) 3 / 1,144,940 |
0.00026% |
African/African American 144 / 24,282 |
0.59% |
Admixed American 10 / 27,790 |
0.036% |
Remaining individuals 1 / 5,870 |
0.017% |
African/African American 10 / 1,020 |
0.98% 1 hom |
