APC or MUTYH mutations account for the majority of clinically well-characterized families with FAP and AFAP phenotype and patients with more than 30 adenomas.

Patients presenting familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP) or multiple colorectal adenomas (MCRAs) phenotype are clinically difficult to distinguish. We aimed to genetically characterize 107 clinically well-characterized patients with FAP-like phenotype, and stratified according to the recent guidelines for the clinical management of FAP: FAP, AFAP, MCRA (10-99 colorectal adenomas) without family history of colorectal cancer or few adenomas (FH), MCRA (10-99) with FH, MCRA (3-9) with FH. Overall, APC or MUTYH mutations were detected in 42/48 (88%), 14/20 (70%) and 10/38 (26%) of FAP, AFAP and MCRA patients, respectively. APC and MUTYH mutations accounted for 81% and 7% of FAP patients and for 30% and 40% of AFAP patients, respectively. Notably, MCRA patients did not present APC mutations. In 26% of these patients, an MUTYH mutation was identified and the detection rate increased with the number of adenomas, irrespectively of family history, being significantly higher in MCRA patients presenting more than 30 adenomas [7/12 (58%) vs 2/14 (14%), p = 0.023]. We validate the recently proposed guidelines in our patient's cohort and show that APC or MUTYH germline defects are responsible for the majority of clinically well-characterized patients with FAP and AFAP phenotype, and patients with more than 30 colorectal adenomas. The different mutation frequencies according to family history and to the number of adenomas underscore the importance of an adequate familial characterization, both clinically and by colonoscopy, in the management of FAP-like phenotypes. The phenotypes of the mutation-negative patients suggest distinct etiologies in these cases.