POLE and neoplasm: Taking into account several lines of evidence (functional data, tumor mutation burden and signatures, in silico predictors, cosegregation, and case–control data), and applying the ACMG/AMP guidelines for variant classification, POLE p.Met294Arg was classified as pathogenic; POLE p.Asp287Glu, POLE p.Asn336Ser, POLD1 p.Arg352Cys, and POLD1 p.Arg521Gln as likely benign; and POLE p.Ile307Val, p.Gly380Cys, p.Lys425Arg, and p.Ala426Val, and POLD1 p.Ile307Met, p.Ile325Val, and p.Arg525Trp as variants of unknown significance (VUS) (Table 1).