Design and validation of a next generation sequencing assay for hereditary breast and ovarian cancer

Hereditary breast and ovarian cancer syndrome, caused by a germline deleterious variant in the BRCA1 or BRCA2 genes, is characterized by an increased risk for breast, ovarian, pancreatic and other cancers. Identification of those who have a BRCA1/2 mutation is important so that they can take advantage of genetic counseling, screening, and potentially life-saving prevention strategies. We describe the design and analytic validation of the Counsyl Inherited Cancer Screen, a next-generation-sequencing-based test to detect pathogenic variation in the BRCA1 and BRCA2 genes. We demonstrate that the test is capable of detecting single-nucleotide variants (SNVs), short insertions and deletions (indels), and copy-number variants (CNVs, also known as large rearrangements) with zero errors over a 96-sample validation set consisting of samples from cell lines and deidentified patient samples, including the well-characterized NA12878 sample from HapMap/1000 Genomes.