Chubb et al. screened a selected population of familial early-onset CRC cases, and concluded that about 0.5 percent of this population carries a pathogenic or likely pathogenic variant in POLE or POLD1. Based on the assumption that this population of familial early-onset CRC cases could completely be explained by high-penetrant predispositions and that up to 10% of the CRCs can be explained by rare genetic predispositions [8,77], we anticipate that novel high-penetrant variants for hCRC and polyposis will have a MAF lower than 0.0005, or will be completely absent in the general population. Here, POLD1 is linked to colorectal carcinoma.