Two groups have analyzed data from the Cancer and Steroid Hormone (CASH) Study, a large case-control study initiated in 1981. In this study group, 11% of breast cancer patients reported a first-degree relative with breast cancer, compared with 5% of control individuals. Using these data, Claus estimated that 36% of breast cancer among women aged 20–29 years is attributable to a single dominant susceptibility gene, with this fraction decreasing to less than 1% for women aged 80 years.

Analysis of women diagnosed with breast cancer before age 40 years suggests that approximately 10% of such American women have a BRCA1 mutation, whereas the prevalence of BRCA2 mutations may be much lower in this group. Results from the only population-based case-control study of BRCA1 mutations suggest that BRCA1 accounted for 3.3% of breast cancer in a group of women not selected for early age of onset. In summary, current estimates place the percentage of breast cancer cases directly attributable to inherited factors at 5% to 10%; further studies are needed to refine these estimates.

Autosomal Dominant Inheritance

Mendelian diseases are defined as those diseases that are the result of a single mutated gene inherited in the simple pattern described by Mendel in 1865 during his study of hybrid garden peas. In his 1901 text Versuche uber Pflanzenhybriden, Mendel described these principles as follows: “Those characteristics that are transmitted entire, or almost unchanged by hybridization . . . are termed dominant, and those that become latent in the process are termed recessive.” To date, all studies of inherited susceptibility to breast cancer have suggested that the predominant breast cancer susceptibility genes are transmitted in an autosomal dominant manner, and the identification of at least five such genes has born out this hypothesis.

Many of the most common genetic disorders of adult life are autosomal dominant diseases; these include familial colon cancer syndromes, polycystic kidney disease, familial hypercholesterolemia, Huntington’s disease, and neurofibromatosis.

In this setting, an individual could have one of three possible genotypes: carrier of two nonmutant gene copies, called alleles (homozygous normal), or carrier of one (heterozygous) or two (homozygous) mutant alleles and therefore affected or at risk of being affected based on the penetrance of the gene. Penetrance is the likelihood that the effect of a mutation will become clinically apparent. Individuals carrying two copies of an autosomal dominant disease-related gene are extremely rare, partly because of the mathematical probability of mating between heterozygotes and partly because of the potential for a lethal defect in a homozygous affected fetus.