Performance of Multi-Gene Panels for Familial Cancer Screening in Clinical Cases: The ColoSeq and BROCA Experience. B. H. Shirts1, S. Casadei2, A. Jacobson1, E. Turner1, J. F. Tait1, M. C. King2,3, T. Walsh2, C. C. Pritchard1 1) Laboratory Medicine, University of Washington, Seattle, WA; 2) Medicine, Division of Medical Genetics, University of Washington, Seattle, WA; 3) Genome Sciences, University of Washington, Seattle, WA.

   We report the clinical performance of next-generation sequencing for hereditary cancer risk using ColoSeq and BROCA. This report includes all 356 sequential cases tested with the 19 gene ColoSeq panel and all 928 sequential cases tested with the 51 gene BROCA panel between November 2011 and February 2014. We classify variants based on consensus of four experts who consider all published and database information. We use a Bayesian framework integrating all available patient and family cancer history. Of providers ordering ColoSeq or BROCA, >95% were genetics specialists and 98% provided cancer history and/or pedigree data. Rates of positive results differed substantially by patient and family history. Actionable mutations in BROCA genes other than BRCA1 and BRCA2 were detected in 10% of patients (with or without cancer) with previous testing for BRCA1 and BRCA2 and in 15% of breast cancer patients with no previous sequencing. Overall, of 928 BROCA tests, 118 (13%) revealed pathogenic or very likely pathogenic variants, and 94 (10%) yielded either variants of uncertain significance in established cancer predisposition genes or clearly deleterious variants in emerging genes. Of 356 ColoSeq tests, 58 (16%) revealed pathogenic or likely pathogenic variants, and 48 (13%) carried either variants of uncertain significance in established cancer risk genes or clearly deleterious variants in emerging genes. Selective providers had positive results at a rate substantially higher than average for both ColoSeq and BROCA tests. We evaluated the benefit of the multi-specialist review and signout process in a subset of cases. Multi-specialist review of all variants increased sensitivity of testing, led to identification of additional actionable variants in 2-5% of cases, and decreased the number of variants of uncertain significance reported. Comprehensive multi-gene testing for patients at risk for inherited cancer syndromes is a complex process that benefits from accurate clinical histories and multiple skilled geneticists evaluating each variant. In our experience, the proportion of patients with actionable mutations depends on the panel of genes tested, patient population, provider selectivity, and combined experience of geneticists evaluating variants. We find that the number of variants assigned "uncertain significance" is less dependent on the number of genes tested than on patient population and combined experience of the geneticists evaluating the variants.

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