An evaluation of BRCA1 and BRCA2 founder mutations penetrance estimates for breast cancer among Ashkenazi Jewish women

Purpose: Three founder mutations in BRCA1 or BRCA2 genes increase breast cancer risk among Ashkenazi Jewish women. Reported estimates of the magnitude of this risk vary widely. We describe an integrated approach for assessing the plausibility of these estimates. Methods: Our approach integrates four epidemiologic parameters: (1) the proportion of all breast cancer cases with a founder mutation, (2) the proportion of women that carry one of these mutations, (3) the proportion of women with a mutation that develops cancer, and (4) the number of women who will develop cancer, regardless of mutation status. We then assess the published estimates of the proportion of Ashkenazi Jewish women with a mutation that develops cancer in the context of the other three parameters. Results: Penetrance for the founder mutations by ages 40, 50, and 70 are approximately 7%, 20%, and 40%, respectively. In two of the four published studies that evaluated at least two of the four parameters, penetrance estimates were internally consistent with the other three parameters and were also consistent with our consensus estimate. The third study had incomplete data. In the fourth study, the penetrance estimate was not internally consistent with the other three parameters, nor was it consistent with the consensus estimate. Conclusions: The four epidemiologic parameters are interdependent and can be used to test the plausibility of any one parameter. Based on the range of breast cancer penetrance estimates for BRCA1 and BRCA2 founder mutations derived by our approach, recently reported penetrance estimates appear to be overestimated.