Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis
Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.
KeywordsInherited cancer Genetic testing MAP MUTYH FAP
Compliance with ethical standards
Conflict of interest
Erin G. Sutcliffe, Amanda Bartenbaker Thompson, Megan L. Marshall, Maegan E. Roberts, Lisa R. Susswein, Ying Wang are employed by GeneDx/BioReference Laboratories, Inc./OPKO Health, and have salary as the only disclosure. Kathleen S. Hruska, Benjamin D. Solomon are employed by and have stock ownership or options in GeneDx/BioReference Laboratories, Inc./OPKO Health. Amy R. Stettner and Rachel T. Klein have no conflicts of interest to disclose.
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