Risk estimation as a decision-making tool for genetic analysis of the breast cancer susceptibility genes

For genetic counselling of a woman on familial breast cancer, an accurate e valuation of the probability that she carries a germ-line mutation is neede d to assist:in making decisions about genetic-testing. We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research fam ilies or counselled for familial breast cancer, representing a broad range of family structures. Screening was performed in affected women from 618 fa milies for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutat ions, using different methods including SSCP, CSGE, DGGE, FAMA and PTT anal ysis followed by direct sequencing. Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families. The probability of bei ng a carrier of a dominant breast cancer gene was calculated for the screen ed individual under me established genetic model for breast cancer suscepti bility, first, with parameters for age-specific penetrances for breast canc er only [7] and, second, with age-specific penetrances for ovarian cancer i n addition [20]. Our results indicate that the estimated probability of car rying a dominant breast cancer gene gives a direct measure of the likelihoo d of detecting mutations in BRCA1 and BRCA2. For breast/ovarian cancer fami lies, the genetic model according to Narod et al. [20] is preferable for ca lculating the proband's genetic risk, and gives detection rates that indica te a 50% sensitivity of the gene test. Due to the incomplete BRCA2 screenin g of the families, we cannot yet draw any conclusions with respect to the b reast cancer only families.