Moderate-Penetrance Predisposition to Breast Cancer

Purpose of Review: Research over the past 25 years has revealed much about the architecture of predisposition to breast and ovarian cancer. There is now a general understanding that there are three broad categories of germline variation that may increase risk. First, there are the “high-penetrance” genes associated with a relative risk for cancer of greater than 5 and demonstrating an autosomal dominant pattern of inheritance. At the other end of the spectrum are “low-penetrance” common variants. These variants are associated with minor increases in risk (commonly less than a relative risk of 1.5). The third group of genes are “moderate-penetrance” genes, with pathogenic variants seen rarely in the general population (commonly < 1%) and relative risks for cancer generally between 2 and 5. Moderate-penetrance genes are the focus of this review. Recent Findings: With the advent of multigene panel testing based on next-generation (or massively parallel) sequencing, genetic risk assessment is identifying significant numbers of patients with pathogenic variants in moderate-penetrance genes such as CHEK2, ATM, PALB2, BRIB1, RAD51C, RAD51D, BARD1, and NBN. Risks associated with breast, ovarian, and other cancers are emerging. Summary: The strength of associations between many of these “moderate-penetrance” genes and cancer risk remains somewhat unclear. Risk is likely to be modulated by age, family history, and perhaps specific genotype, further complicating the clinical counseling scenario. There is a clear need for ongoing research in this area, an endeavor that is likely to take time and commitment given the relative rarity of these pathogenic variants. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.