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Cancer Epidemiology Biomarkers & Prevention Vol. 8, 741-747, September 1999
© 1999 American Association for Cancer Research

Population-based Estimate of the Average Age-specific Cumulative Risk of Breast Cancer for a Defined Set of Protein-truncating Mutations in BRCA1 and BRCA21

John L. Hopper2, Melissa C. Southey, Gillian S. Dite, Damien J. Jolley, Graham G. Giles, Margaret R. E. McCredie, Douglas F. Easton, Deon J. Venter and the Australian Breast Cancer Family Study

The University of Melbourne, Centre for Genetic Epidemiology, Carlton, Victoria 3052, Australia [J. L. H., G. S. D., D. J. J.]; Departments of Pathology and Research, Peter MacCallum Cancer Institute, Melbourne, Victoria 3000, Australia [M. C. S., D. J. V.]; Cancer Epidemiology Centre, The Anti-Cancer Council of Victoria, Carlton, Victoria 3053, Australia [G. G. G.]; Cancer and Epidemiology Research Unit, New South Wales Cancer Council, Woolloomooloo, New South Wales 2011, Australia [M. R. E. M.]; Department of Preventive and Social Medicine, University of Otago, Dunedin 9001, New Zealand [M. R. E. M.]; Cancer Research Campaign Genetic Epidemiology Unit, Strangeways Research Laboratories, University of Cambridge, Cambridge, United Kingdom [D. F. E.]; and Department of Pathology, The University of Melbourne, Parkville, Victoria 3052, Australia [D. J. V.]

The average breast cancer risk for carriers of a germ-line mutation in BRCA1 or BRCA2 (penetrance) has been estimated from the multiple-case families collected by the Breast Cancer Linkage Consortium (BCLC) to be {approx}80% to age 70. However, women now being tested for these mutations do not necessarily have the intense family history of the BCLC families. Testing for protein-truncating mutations in exons 2, 11, and 20 of BRCA1 and exons 10 and 11 of BRCA2 was conducted in a population-based sample of 388 Australian women with breast cancer diagnosed before age 40. Onset of breast cancer was analyzed in the known and potential mutation-carrying first- and second-degree female relatives of cases found to carry a mutation. Of the 18 mutation-carrying cases (9 BRCA1 and 9 BRCA2), only 5 (1 BRCA1 and 4 BRCA2) had at least one affected relative, so family history of breast cancer was not a strong predictor of mutation status in this setting. The risk in mutation carriers was, on average, 9 times the population risk [95% confidence interval (CI), 4–23; P < 0.001]. Penetrance to age 70 was 40% (95% CI, 15–65%), about half that estimated from BCLC families. By extrapolation, {approx}6% (95% CI, 2–20%) of breast cancer before age 40 may be caused by protein-truncating mutations in BRCA1 or BRCA2. Breast cancer risk in BRCA1 or BRCA2 mutation carriers may be modified by other genetic or environmental factors. Genetic counselors may need to take into account the family history of the consultand.




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