POLE and breast cancer: In our study, two families carrying POLE and POLD1 VUS also carried pathogenic variants in ATM and CHEK2, two genes that confer a moderate risk of breast cancer.37,38 The aggressive phenotype developed by the POLD1 p.Arg525Arg and ATM (p.Ser2407*) carrier supports a cumulative effect of the two variants, while that may not be the case for the carriers of POLE p.Ala426Val (VUS) and CHEK2 c.593–1G>T, where two of the three carriers developed late-onset CRC.