Familial adenomatous polyposis (FAP) and the Lynch syndrome are the most common and well-known high-penetrance genetic syndromes that confer inherited risks of colorectal cancer (CRC). In each case, the culpable genes were identified by linkage studies, inactivating mutations found in the germlines of affected individuals, and the mutations tracked through the families to demonstrate Mendelian patterns of inheritance.1–5 However, not all familial CRC (fCRC) can be linked to FAP or the Lynch syndrome, which has led to the subsequent identification of multiple “new” fCRC genes, most of which are rare and have reduced penetrance for CRC compared with the first 2 diseases.