Introduction: A strong family history of breast and/or ovarian cancer can often be explained by small insertions, deletions, or substitutions in BRCA1 or BRCA2 and large genomic rearrangements in BRCA1. However, there is little evidence that genomic rearrangements are a major factor in BRCA2 associated breast cancer and the frequencies of rearrangements in BRCA1 in large clinic based populations are unknown. Objective: To investigate the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large clinic based population at high risk of developing breast and/or ovarian cancer. Methods: Multiplex ligation dependent probe amplification was used to comprehensively screen BRCA1 and/or BRCA2 in 312 index cases. Results: Three novel deletions detected in BRCA2 were found exclusively in families with at least one case of male breast cancer. Novel rearrangements in BRCA1 were detected mostly in families with both breast and ovarian cancer. Families with these mutations were significantly younger at average age of cancer diagnosis. Conclusion: Screening for large genomic rearrangements in both BRCA1 and BRCA2 is strongly supported by this study, in particular in multiple case breast/ovarian families with a young age of onset (BRCA1) and families containing at least one case of male breast cancer (BRCA2). Inheritance of a germline mutation in a cancer susceptibility gene accounts for 5-10% of all breast and ovarian cancer, and a higher proportion of cancers associated with a strong family history of the disease. From the initial linkage studies in the early 1990s it was predicted that mutations in BRCA1 and BRCA2 would account for a large proportion of multiple case families. 1 However, despite extensive mutation analysis, the rate of detection of mutations in these genes rarely rises above 30% in the family cancer clinical setting and has never reached the expected high frequency, even in families with multiple cases of the disease in successive generations. Until recently, the testing of BRCA1 and BRCA2 has been focussed on the identification of point mutations or small deletions and insertions.2 Another mechanism of gene inactivation, namely the rearrangement of large tracts of genomic DNA, may be responsible for a proportion of the undetected mutations and many families previously found to be mutation negative might harbour hitherto undiscovered rearrangements. [3][4][5] Homologous recombination between repeated DNA sequences is believed to be a major cause of the genetic instability that results in genomic deletions, duplications, or other rearrangements. The high density of Alu repeat sequences in BRCA1 (42%) and both Alu (20%) and non-Alu (27%) repetitive DNA in BRCA2 supports the likelihood that these genes may be susceptible to inactivation by homologous recombination. 6 The first rearrangement described in BRCA1 was a 1 kb deletion that included the loss of exon 17. 7 Since that time, up to 30 different genomic rearrangements, both deletions and duplications, ranging in size from 510 bp to 37 kb, have...

If the risk of disease is not the same for all germline mutations in a given gene, or if there are other familial modifiers of risk in carriers, then family-historybased estimates of average risk for detected mutations in that gene will depend on how carriers are sampled. Risk may also depend on the site or type of mutation. We studied 51 families with strong histories of breast cancer who attended Australian family cancer clinics and in which a germline mutation in BRCA1 or BRCA2 had been identified (28 and 23 families, respectively). Breast cancer risk in carriers was estimated under maximum likelihood theory, using information from all family members including those not tested, with adjustment for ascertainment by conditioning on genotype of the proband and family phenotype. The average cumulative risk of breast cancer for mutations in either BRCA1 or BRCA2 was 27% (95% confidence interval 16-43%) to age 50 and 64% (44-83%) to age 70. When grouped, the incidence in carriers was on average 17 (10-30) times that in non-carriers, independent of gene or mutation type (hazard ratios: 11 (4-29) for BRCA1, 23 (12-43) for BRCA2 (P for difference = 0.23); 13 (6-29) for protein-truncating mutations, 30 (9-104) for missense mutations and 30 (10-90) for splice-site mutations). For missense mutations, this was equivalent to a cumulative risk to age 70 of 83% (40-100%) and was due in part, but not totally, to the missense mutations 300 T>G in BRCA1 and 4486 G>T in BRCA2, which were individually found to be associated with high risk (P<0.001). Mutations in the central region of BRCA1 may be associated with a lower risk. The issue of the pathogenicity of specific variants may be addressed analytically providing there are one or more suitably informative families with that mutation.