n Abstract: Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Most of these cases will be found to be due to a BRCA germline mutation. An estimated additional 15-20% of those affected with BC will have one or more first-and ⁄ or second-degree relatives with BC. Therefore, when these numbers are combined, familial BC risk accounts for approximately 20-25% of the total BC burden. However, because of the often limited information on family history in the etiologic assessment of BC, this may be an underestimate. Confounding factors include its phenotypic and geno-typic heterogeneity, given the association of HBC with a plethora of differing cancer syndromes. Its most common occurrence is its association with ovarian cancer in the so-called hereditary breast-ovarian cancer syndrome due to BRCA1 and BRCA2 mutations. More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma. Importantly, the age-adjusted incidence of BC in women in the United States fell sharply, by 6.7%, in 2003, when compared with the rate identified in 2002. We postulate that increasing knowledge about the genetics of BC may have partially contributed to the identification of high-risk patients who thereby may have benefited significantly from early diagnosis. n Key Words: BRCA1, BRCA2, genotypic and phenotypic heterogeneity, hereditary breast cancer, hereditary breast-ovarian cancer H ereditary breast cancer (HBC) accounts for approximately 10% of the total BC burden, while an estimated additional 15-20% of those affected with BC will have a positive family history of this disease (1). In a previous study (2) of 328 consecutively ascertained BC patients, where family history was intensively pursued, findings were remarkably similar, showing 23% to be familial, that is, one or more first-and ⁄ or second-degree relatives of the proband with BC, and 9% to be putative hereditary. Predictably, a subset of familial BCs, and even some so-called ''sporadics,'' will, with rigorous family history assessment and ⁄ or discovery of new low-penetrant germline mutations (3,4), turn out to be hereditary. Clearly, intensive family history documentation in patients with BC should provide the potential for improved cancer control gain through the identification of candidates for highly organ-targeted surveillance and management measures. The advent of BRCA mutation testing, which became available in the mid-1990s (2), now allows a much more precise estimation of high-risk candidates for targeted surveillance and management (5). A significant portion of HBC-prone families are characterized by the more common hereditary breast-ovarian cancer (HBOC) syndrome and carry BRCA1 and BRCA2 mutations which, in fact, account for at least 30% of all HBC. Therefore, about 70% of the HBC burden lacks these mutations (6,7). In spite of an intensive search at many cen...