To date, five moderate-risk breast cancer susceptibility genes have been convincingly identified: CHEK2, ATM, BRIP1, PALB2, and NBS1. Moderate-risk breast cancer alleles confer increased breast cancer risks of two to fourfold compared to the 10% risk in the general population. In contrast to the high-risk BRCA1 and BRCA2 genes, moderate-risk genes typically have a limited number of variants that confer breast cancer risks. The prevalence of the variants usually varies widely among different geographical or ethnic populations, ranging from essentially absent up to 1.5% (i.e. 'rare' variants). Since moderate-risk breast cancer alleles are clinically not recognizable when inherited as single mutant, one usually encounters them in a polygenic setting and consequently in incomplete cosegregation with the breast cancer phenotype. As a result, discovery of moderate-risk breast cancer genes requires conclusive statistical evidence from association studies of hundreds of breast cancer cases and population-matched controls.

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Journal Current Opinion in Genetics & Development
Hollestelle, A, Wasielewski, M, Martens, J.W.M, & Schutte, A.E.M. (2010). Discovering moderate-risk breast cancer susceptibility genes. Current Opinion in Genetics & Development (Vol. 20, pp. 268–276). doi:10.1016/j.gde.2010.02.009