POLE c.1277C>T (p.Ala426Val) (MAFgnomAD_NFE = 0.0034%), affecting a highly conserved residue within the Exo IV motif active site, was identified in a male diagnosed with CRC and multiple adenomas at age 44 and with renal cancer at 49, and in his CRC-affected paternal uncle. Here, POLE is linked to colorectal carcinoma.