The relatively high percentage of MMR-w.t. patients identified only based on personal and familial history of LS-associated tumors (Amsterdam criteria II), in addition to the lower sensitivity of the selection strategy, may probably be due to the presence of uninvestigated germline mutations in other CRC susceptibility genes such as MUTYH, POLE, POLD1, PTEN, STK11, TP53, SMAD4, BMPR1A (56–58). Here, SMAD4 is linked to colorectal carcinoma.