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...