Breast cancer genes: beyond BRCA1 and BRCA2.

Breast cancer (BC) is a heterogeneous disease. The majority of breast cancer cases (about 70 percent) are considered sporadic. Familial breast cancer (about 30 percent of patients), often seen in families with a high incidence of BC, has been associated with a number of high-, moderate-, and low-penetrance susceptibility genes. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, PTEN and TP53, that are responsible for inherited syndromes. Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP1 (FANCJ), PALB2 (FANCN) and RAD51C (FANCO), are associated with moderate BC risk. Genome wide association studies (GWAS) in BC revealed a number of common low penetrance alleles associated with a slightly increased or decreased risk of BC. Currently, only high penetrance genes are used in clinical practice on a wide scale. Due to the development of next generation sequencing technologies, it is envisaged that all familial breast cancer genes will be included in the genetic test. However, additional research in clinical management of moderate and low-risk variants is needed before full implementation of multi-gene panel testing into clinical work-flows. In this review, we focus on the different components of familial breast cancer risk.