Besides RPS20, the anecdotal identification of germline pathogenic variants in some polyposis genes (MUTYH, POLE, POLD1, BMPR1A) in cases with nonpolyposis CRC phenotypes, the low or marginal CRC risks reported for other hereditary cancer genes such as ATM, CHEK2, TP53, and BRCA1, or the low-penetrance APC variant I1307K [2–6], no other genes have been unequivocally associated with MMR-proficient nonpolyposis CRC predisposition [7]. Here, POLE is linked to colorectal carcinoma.