Pathogenic Variant Spectrum in Newly Described Cancer Genes on Next Generation Cancer Panels. L. Susswein, L. Vincent, R. Klein, J. Booker, M. L. Cremona, P. Murphy, K. Hruska GeneDx, Gaithersburg, MD.

   Background: The past few years have witnessed a rapid expansion of the number of genes available on clinical cancer genetic tests. Twelve of the genes on Next Generation Sequencing (NGS) panels were identified more recently as associated with cancer risk: AXIN2, ATM, BARD1, BRIP1, CHEK2, CDK4, FANCC, NBN, PALB2, RAD51C, RAD51D, and XRCC2.
   Methods: Since the launch of the NGS Cancer panels at GeneDx in August 2013, 3363 individuals have been tested for panels that included some or all of these newly described genes. We retrospectively queried all results to assess the spectrum of pathogenic variants identified within this group of newly described cancer genes.
   Results: Overall, 515 different germline variants were identified among these 12 genes. The gene with the highest number of variants identified was ATM, also the largest gene of the group, with 155 different variants. PALB2 had the next highest degree of variation with 68 variants, followed by CHEK2 with 59 and BRIP1 with 58. Of the variants classified as pathogenic/likely pathogenic (P/LP), 79% were truncating (frameshift, nonsense, splice mutations, and large deletions). Four genes (ATM, BRIP1, CHEK2, and PALB2) were found to have >10 different variants classified as P/LP. While all P/LP variants in PALB2 were truncating (n=16), the other genes had some missense variants that were classified as P/LP (ATM: 3 missense of 29 total P/LP variants, BRIP1: 1 of 10, CHEK2: 8 of 15). AXIN2 and CDK4 were the only two genes in which no P/LP variants were identified; all were missense and classified as variants of unknown significance (n=13 and 3, respectively).
   Conclusion: Continued utilization of multi-gene NGS panels will enable better characterization of these newer genes. Such knowledge will allow for better understanding of the clinical consequence of mutations in these genes.

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