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Classifying variants of CDKN2A using computational and laboratory studies

✍ Scribed by Peter J. Miller; Sekhar Duraisamy; Joan A. Newell; Philip A. Chan; Mark M. Tie; Amy E. Rogers; Claire K. Ankuda; Genevieve M. von Walstrom; Jeffrey P. Bond; Marc S. Greenblatt

Publisher: John Wiley and Sons
Year: 2011
Tongue: English
Weight: 337 KB
Volume: 32
Category: Article
ISSN: 1059-7794
DOI: 10.1002/humu.21504

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✦ Synopsis

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 495% 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.

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