A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer 
families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and 
BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such 
families. The extent to which major genomic rearrangements in BRCA contribute to 
breast and ovarian cancer in the Ashkenazim is not well understood. We 
identified AJ individuals with breast and/or ovarian cancer undergoing 
hereditary breast/ovarian cancer risk assessment since 2006 without evidence of 
a deleterious mutation on BRCA gene sequencing who were screened for major gene 
rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of 
identifying a deleterious BRCA mutation was estimated using the Myriad II model. 
We identified 108 affected individuals who underwent large rearrangement testing 
(80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The 
mean estimated AJ specific pre-test probability of a deleterious mutation in 
BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were 
identified in either the entire group or in the 26 subjects with pre-test 
mutation prevalence estimates exceeding 30%. Major gene rearrangements involving 
the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited 
predisposition to breast and ovarian cancer in the Ashkenazim.