POLE and POLD1 germline variants affecting the exonuclease domain required for polymerase proofreading, e.g. POLE p.(L424V) and POLD1 p.(S478N), were initially reported to predispose to colorectal adenomas and carcinomas [8], and some of these variants, e.g. POLE p.(P286R), p.(V411L), and p.(L424V), and POLD1 p.(C319Y), have been experimentally associated with hypermutation [43]. This evidence concerns the gene POLE and carcinoma.