Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 andBRCA2

The average breast cancer risk for carriers of a germ-line mutation in BRCA 1 or BRCA2 (penetrance) has been estimated from the multiple-case families collected by the Breast Cancer Linkage Consortium (BCLC) to be similar to 8 0% to age 70. However, women now being tested for these mutations do not ne cessarily 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 Australia n 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 muta tion-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 mutatio n carriers was, on average, 9 times the population risk [95% confidence int erval (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, similar to 6% (95% CI, 2-20%) of breast cancer before age 40 may be caused by prote in-truncating mutations in BRCA1 or BRCA2. Breast cancer risk in BRCA1 or B RCA2 mutation carriers may be modified by other genetic or environmental fa ctors, Genetic counselors may need to take into account the family history of the consultand.