Breast–Ovarian Hereditary Cancer Syndrome: Beyond BRCA1 and BRCA2

Although BRCA1 and BRCA2 remain the backbone for germline DNA testing of patients with breast cancer (BC) or ovarian cancer (OC), there are a number of other genes with proven or potential clinical significance. PALB2 is associated with an elevated risk of BC, whereas pathogenic variants (PVs) in RAD51C, RAD51D, and BRIP1 are mainly relevant to OC development. Some germline findings are helpful in guiding therapeutic decisions: for example, PALB2, RAD51C, and RAD51D germline PVs render tumors sensitive to PARP inhibitors (PARPi), whereas cancers arising in PTEN heterozygotes are likely to be responsive to AKT down-regulators. CHEK2, ATM, BLM, and NBN PVs result in only a two-fold or even lower excess of cancer risk. However, the incorporation of these genes in DNA testing panels may occasionally lead to the identification of individuals with biallelic germline inactivation; these patients have a severe disease phenotype and thus require intensive medical intervention. The accumulation of data on “non-BRCA” BC- and OC-predisposing genes is complicated due to the rarity of their alterations, significant interethnic variations in population frequency of relevant PVs, heterogeneity of disease subtypes, etc. The use of extended gene panels, which pool together both clinically validated cancer-associated genes and “candidate” genes with potential but unproven significance, is likely to be a prevailing diagnostic approach in the next few years; therefore, proper attitudes towards accumulation and interpretation of genetic data are important.