A Systematic Comparison of Traditional and Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Genes in More Than 1000 Patients Stephen.

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A Systematic Comparison of Traditional and Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Genes in More Than 1000 Patients Stephen E. Lincoln, Yuya Kobayashi, Michael J. Anderson, Shan Yang, Andrea J. Desmond, Meredith A. Mills, Geoffrey B. Nilsen, Kevin B. Jacobs, Federico A. Monzon, Allison W. Kurian, James M. Ford, Leif W. Ellisen The Journal of Molecular Diagnostics Volume 17, Issue 5, Pages 533-544 (September 2015) DOI: 10.1016/j.jmoldx.2015.04.009 Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 1 Pathogenic variants by subpanel. Number of cases with pathogenic or likely pathogenic variants observed in BRCA1/BRCA2 and in 27 other genes (A) and in these 27 other genes by subpanel (B). The clinical referral cohort represents our best estimate of prevalence in a clinically representative population. The Journal of Molecular Diagnostics 2015 17, 533-544DOI: (10.1016/j.jmoldx.2015.04.009) Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 2 Prevalence of variants of unknown significance (VUSs). Cumulative fraction of clinical cases with one or more VUSs reported, irrespective of pathogenic variants observed, as the scope of testing increases. The Journal of Molecular Diagnostics 2015 17, 533-544DOI: (10.1016/j.jmoldx.2015.04.009) Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 3 Pathogenic variants by type. Pathogenic variants (n = 260) among the clinical cases (n = 1062) by variant type. A significant fraction (13.4%) of the pathogenic variants are of types known to be technically challenging for next-generation sequencing, even though they are a small fraction (<0.1%) of the total set of variants. Single-nucleotide variant (SNV) and copy number variant (CNV) are shown. The Journal of Molecular Diagnostics 2015 17, 533-544DOI: (10.1016/j.jmoldx.2015.04.009) Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 4 Accumulation of new variants requiring interpretation. Accumulation of new variants in 29 genes requiring clinical interpretation as patients are added (n = 1062). The slope at the end is 0.7 new variants per patient. Variants with high minor-allele frequencies (>3% in the 1000 Genomes Project data) are automatically classified as benign and are not included in this analysis. Data shown are a smoothed average over 10 randomized orders of patients. The Journal of Molecular Diagnostics 2015 17, 533-544DOI: (10.1016/j.jmoldx.2015.04.009) Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions