While the breast tumor from the POLE p.Gly380Cys carrier showed no hypermutation (0.67 Mut/Mb), a breast tumor from a POLE p.Asp287Glu carrier, a melanoma from a POLE p.Ile307Val carrier, the MMR-proficient CRC from the POLE p.Ala426Val and CHEK2 c.593–1G>T carrier, and a CRC from a POLD1 p.Arg521Gln carrier showed hypermutation but none of the POLE/D1-associated mutational signatures (Fig. 4; Supplementary Table S7). Here, MRC1 is linked to breast neoplasm.