Probability of Carrying a Mutation of Breast-Ovarian Cancer Gene BRCA1 Based on Family History

Background: Heritable mutations of the breast cancer gene BRCA1 are rare, occurring in fewer than 1% of women in the general population, and therefore account for a small proportion of cases of breast and ovarian cancers. Nevertheless, the presence of such mutations is highly predictive of the development of these cancers. Purpose: We developed and applied a mathematic model for calculating the probability that a woman with a family history of breast and/or ovarian cancer carries a mutation of BRCA1. Methods and Results: As a basis for the model, we use Mendelian genetics and apply Bayes’ theorem to information on the family history of these diseases. Of importance are the exact relationships of all family members, including both affected and unaffected members, and ages at diagnosis of the affected members and current ages of the unaffected members. We used available estimates of BRCA1 mutation frequencies in the general population and age-specific incidence rates of breast and ovarian cancers in carriers and noncarriers of mutations to estimate the probability that a particular member of the family carries a mutation. This probability is based on cancer statuses of all first- and second-degree relatives. We first describe the model by considering single individuals: a woman diagnosed with breast and/or ovarian cancer and also a woman free of cancer. We next considered two artificial and two actual family histories and addressed the sensitivity of our calculations to various assumptions. Particular relationships of family members with and without cancer can have a substantial impact on the probability of carrying a susceptibility gene. Ages at diagnosis of affected family members and their types of cancer are also important. A woman with two primary cancers can have a probability of carrying a mutation in excess of 80%, even with no other information about family history. The number and relationships of unaffected members, along with their current ages or ages at death, are critical determinants of one’s carrier probability. An affected woman with several cancers in her family can have a probability of carrying a mutation that ranges from close to 100% to less than 5%. Conclusion: Our model gives informative and specific probabilities that a particular woman carries a mutation. Implications: This model focuses on mutations in BRCA1 and assumes that all other breast cancer is sporadic. With the cloning of BRCA2, we now know that this assumption is incorrect. We have adjusted the model to include BRCA2, but the use of this version must await publication of penetrance data for BRCA2, including those for male breast cancer that are apparently associated with BRCA2 but not with BRCA1. The current model is, nevertheless, appropriate and useful. Of principal importance is its potential and that of improved versions for aiding women and their health care providers in assessing the need for genetic testing. [J Natl Cancer Inst 1997;89:227-37] There are approximately 180 000 new cases of breast cancer diagnosed each year in the United States. Approximately 45 000 women die of the disease annually. Although only about 26 000 cases of ovarian cancer are diagnosed each year, proportionately more women (14 000 annually) die of ovarian cancer (1). It is estimated that 2% of all breast cancers and 10% of ovarian cancers occur in women who carry a mutation in the BRCA1 susceptibility gene for breast cancer (2). The prevalence of mutations at BRCA1 has been estimated to be 0.04%-0.20% in the general population (3), but prevalence may vary, depending on racial or ethnic group (4). Approximately 85% of female carriers will develop breast cancer and 63% will develop ovarian cancer by the age of 70 years (2). Moreover, these two cancers seem to be statistically independent (2). In particular, based on these estimates, for female carriers who live to age 70 years, about 95% [o r1˛( 1 ˛0.85) (1 ˛ 0.63)] have developed one or the other cancer and about 54% (or 0.85 ◊ 0.63) have both cancers. The high penetrances of breast and ovarian cancers among women with BRCA1 mutations mean that family history of these diseases is a strong indicator of whether a mutation is present in the family. This article presents a method for finding the probability that a particular family member carries a mutation at BRCA1 on the basis of her family’s history of these two diseases.