Low-Penetrance Predisposition to Breast and Ovarian Cancer
Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed above account for less than 25% of the familial risk of breast cancer. Despite intensive genetic linkage studies, there do not appear to be other BRCA1/BRCA2-like high-penetrancegenes that account for a significant fraction of the remaining multiple-case familial clusters. These observations suggest that the remaining breast cancer susceptibility is polygenic in nature, meaning that a relatively large number of low-penetrance genes are involved. On its own, each low-penetrance locus would be expected to have a relatively small effect on breast cancer risk and would not produce dramatic familial aggregation or influence patient management. However in combination with other genetic loci and/or environmental factors, particularly given how common these can be, variants of this kind might significantly alter breast cancer risk. These types of genetic variations are sometimes referred to as "polymorphisms," meaning that the gene or locus occurs in several "forms" within the population (and more formally defined as polymorphic when a specific variation in a given locus occurs in more than 1% of the population). Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed "disease-associated polymorphisms" or "functionally relevant polymorphisms." This polygenic model of susceptibility is consistent with the observed patterns of familial aggregation of breast cancer. Although the clinical significance and causality of associations with breast cancer are often difficult to evaluate and establish, genetic polymorphisms may account for why some individuals are more sensitive than others to environmental carcinogens.
Polymorphisms underlying polygenic susceptibility to breast cancer are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to "high-penetrance" variants or alleles that are typically associated with more severe phenotypes, for example those BRCA1/BRCA2 mutations leading to an autosomal dominant inheritance patterns in a family. The definition of a "moderate" risk of cancer is arbitrary, but it is usually considered to be in the range of a relative risk of 1.5 to 2.0. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the general population, their contribution to cancer risk overall is estimated to be much greater than the attributable risk in the population from mutations in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible. There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.