title: Classifying variants of CDKN2A using computational and laboratory studies.
abstract: Variants in the CDKN2A tumor suppressor are associated with Familial Melanoma (FM), although for many variants the linkage is weak. The effects of missense variants on protein function and pathogenicity are often unclear. Multiple methods (e.g., laboratory, computational, epidemiological) have been developed to analyze whether a missense variant is pathogenic or not. It is not yet clear how to integrate these data types into a strategy for variant classification. We studied 51 CDKN2A missense variants using a cell cycle arrest assay. There was a continuum of results ranging from full wild-type effect through partial activity to complete loss of arrest. A reproducible decrease of 30% of cell cycle arrest activity correlated with FM association. We analyzed missense CDKN2A germline variants using a Bayesian method to combine multiple data types and derive a probability of pathogenicity. When equal to or more than two data types could be evaluated with this method, 22 of 25 FM-associated variants and 8 of 15 variants of uncertain significance were classified as likely pathogenic with >95% probability. The other 10 variants were classified as uncertain (probability 5-95%). For most variants, there were insufficient data to draw a conclusion. The Bayesian model appears to be a sound method of classifying missense variants in cancer susceptibility genes.
authors.affiliation: Department of Medicine and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Miller
authors.forename: Sekhar
authors.initials: S
authors.lastname: Duraisamy
authors.forename: Joan A
authors.initials: JA
authors.lastname: Newell
authors.forename: Philip A
authors.initials: PA
authors.lastname: Chan
authors.forename: Mark M
authors.initials: MM
authors.lastname: Tie
authors.forename: Amy E
authors.initials: AE
authors.lastname: Rogers
authors.forename: Claire K
authors.initials: CK
authors.lastname: Ankuda
authors.forename: Genevieve M
authors.initials: GM
authors.lastname: von Walstrom
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Bond
authors.forename: Marc S
authors.initials: MS
authors.lastname: Greenblatt
mesh_terms: D001681:Biological Assay; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D019295:Computational Biology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012016:Reference Values
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16