Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q

Mendelian tumour syndromes are caused by rare mutations, which usually lead to protein inactivation. Few studies have determined whether or not the sa me genes harbour other, more common variants, which might have a lower pene trance and/or cause mild disease, perhaps indistinguishable from sporadic d isease and accounting for a considerable proportion of the unexplained inhe rited risk of tumours in the general population. Germline variants at the A PC locus are excellent candidates for explaining why some individuals are p redisposed to colorectal adenomas, but do not have the florid phenotype of familial adenomatous polyposis. We have screened 164 unrelated patients wit h 'multiple' (3-100) colorectal adenomas for germline variants throughout t he APC gene, including promoter mutations. In addition to three Ashkenazi p atients with I1307K, we found seven patients with the E1317Q variant. E1317 Q is significantly associated with multiple colorectal adenomas (OR = 11.17 , 95% CI = 2.30-54.3, p < 0.001), accounting for similar to 4% of all patie nts with multiple colorectal adenomas. In addition, four patients with trun cating APC variants in exon 9 or in the 3' part of the gene were identified . Germline APC variants account for similar to 10% of patients with multipl e adenomas. Unidentified predisposition genes almost certainly exist. We ar gue that it is worthwhile to screen multiple adenoma patients for a restric ted number of germline APC variants, namely the missense changes E1317Q and I1307K (if of Ashkenazi descent), and, if there is a family history of col orectal tumours, for truncating mutations 5' to exon 5, in exon 9 and 3' to codon 1580.