BRCA1 mutations and other sequence variants in a population based sample of Australian women with breast cancer

The frequency, in women with breast cancer, of mutations and other variants in the susceptibility gene, BRCA1, was investigated using a population-bas ed case-control-family study. Cases were women living in Melbourne or Sydne y, Australia, with histologically confirmed, first primary, invasive breast cancer, diagnosed before the age of 40 years, recorded on the state Cancer Registries. Controls were women without breast cancer, frequency-matched f or age, randomly selected from electoral rolls. Full manual sequencing of t he coding region of BRCA1 was conducted in a randomly stratified sample of 91 cases; 47 with, and 44 without, a family history of breast cancer in a f irst- or second-degree relative. All detected variants were tested in a ran dom sample of 67 controls. Three cases with a (protein-truncating) mutation were detected. Only one case had a family history; her mother had breast c ancer, but did not carry the mutation. The proportion of Australian women w ith breast cancer before age 40 who carry a germline mutation in BRCA1 was estimated to be 3.8% (95% CI 0.3-12.6%). Seven rare variants were also dete cted, but for none was there evidence of a strong effect on breast cancer s usceptibility. Therefore, on a population basis, rare variants are likely t o contribute little to breast cancer incidence.