Role ofPOLEandPOLD1in familial cancer

Purpose Germline pathogenic variants in the exonuclease domain (ED) of polymerasesPOLEandPOLD1predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence ofPOLEandPOLD1variants in hereditary cancer are evaluated in this study. Methods POLEandPOLD1were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case-control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. Results Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies