PM2 supporting: gnomAD v4.1 all-comers allele frequency is 1.67e-05, below the 0.0001 threshold, with no homozygotes. PP3 supporting: REVEL 0.749 places this missense change in the PP3 supporting band under the generic in-silico fallback.
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 POLE missense change alters a residue in the polymerase region of the protein, well outside the exonuclease proofreading domain whose germline defects account for POLE-associated polyposis and colorectal cancer predisposition.
PM2 supporting: gnomAD v4.1 all-comers allele frequency is 1.67e-05, below the 0.0001 threshold, with no homozygotes. PP3 supporting: REVEL 0.749 places this missense change in the PP3 supporting band under the generic in-silico fallback.
Ashkenazi Jewish 23 / 29,608 |
0.078% |
European (non-Finnish) 4 / 1,180,040 |
0.00034% |
Ashkenazi Jewish 10 / 10,370 |
0.096% |
European (non-Finnish) 1 / 129,190 |
0.00077% |