Next-generation sequencing for inherited breast cancer risk: counseling through the complexity.

Next-generation sequencing technology affords an unprecedented opportunity to analyze multiple breast cancer susceptibility genes simultaneously. With the incarnation of gene panels that combine testing for moderate- and high-penetrance genes, this technology has given birth to a paradigm shift in clinical genetic test offerings. A transformation in genetic counseling for cancer susceptibility will necessarily follow, with a shift from the traditional approach of single-gene testing to considerations of testing by multi-gene panels. At the same time, however, the opportunity to identify rare lesions underlying hereditary susceptibility has introduced new challenges. Available cancer risk estimates for genes included in panel tests may not be supported by evidence, and there is increased risk of identifying variants of uncertain significance (VUS). Management of individuals with rare pathogenic mutations may be unclear. We provide a summary of available evidence for breast cancer risks conferred by pathogenic mutations in genes commonly included in breast cancer susceptibility panels, as well as a review of limitations and counseling points.