Inherited breast cancer

Inherited mutations in high-risk breast cancer-predisposing genes explain approximately 10 % of all breast cancer cases. Most of these mutations are in the BRCA1 and BRCA2 genes, as part of hereditary breast and ovarian cancer (HBOC). Others are in genes associated with syndromes which include a wider spectrum of malignancies and/or distinct clinical features. Molecular analysis, guided by clinical criteria and application of risk assessment models, currently reveal the underlying cause in roughly half of hereditary breast cancer families. Women who have inherited mutations in the HBOC genes have a high lifetime risk for both breast cancer and ovarian cancer. In BRCA1 and BRCA2 carriers, effective surveillance and prevention measures (such as risk-reduction salpingo-oophorectomy) reduce morbidity and mortality, and mutation status can enable targeted therapy (such as PARP inhibitors).Clinical genetic analysis for suspected inherited predisposition to breast cancer, previously mostly limited to Sanger sequencing of BRCA1 and BRCA2, has been transformed by next-generation sequencing (NGS) technology, which enables rapid and simultaneous analysis of multiple genes. The ability of NGS assays to accurately and cost-effectively detect all classes of mutations, including large rearrangements, offers an important advantage over previous testing strategies. However, clinical interpretation of variants remains a significant challenge even in the well-studied BRCA1 and BRCA2 genes, let alone other breast cancer-associated genes. Testing numerous individuals is revealing an ever greater number of rare variations, whose effect on gene and protein function remains unclear. Reporting such variants of unknown significance is not driven by their clinical utility, and there is an urgent need for improved strategies to assess their functional and clinical effects. Testing genes beyond BRCA1 and BRCA2 is further complicated by the current lack of evidence-based guidelines for surveillance and prevention measures, even for carriers of mutations in genes considered to be clear moderate-risk predisposition genes.Nevertheless, identifying cancer-predisposing mutations is increasingly feasible, will lead to optimized, personalized care for mutation carriers, and is likely to provide insights of broader relevance to cancer.