Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing

The frequency of genomic rearrangements in BRCA1 was assessed in 42 America n families with breast and ovarian cancer who were seeking genetic testing and who were subsequently found to be negative for BRCA1 and BRCA2 coding-r egion mutations. An affected individual from each family was tested by PCR for the exon 13 duplication (Puget et al. 1999a) and by Southern blot analy sis for novel genomic rearrangements. The exon 13 duplication was detected in one family, and four families had other genomic rearrangements. A total of 5 (11.9%) of the 42 families with breast/ovarian cancer who did not have BRCA1 and BRCA2 coding-region mutations had mutations in BRCA1 that were m issed by conformation-sensitive gel electrophoresis or sequencing. Four of five families with BRCA1 genomic rearrangements included at least one indiv idual with both breast and ovarian cancer; therefore, 4 (30.8%) of 13 famil ies with a case of multiple primary breast and ovarian cancer had a genomic rearrangement in BRCA1. Families with genomic rearrangements had prior pro babilities of having a BRCA1 mutation, ranging from 33% to 97% (mean 70%) ( Couch et al. 1997). In contrast, in families without rearrangements, prior probabilities of having a BRCA1 mutation ranged from 7% to 92% (mean 37%). Thus, the prior probability of detecting a BRCA1 mutation may be a useful p redictor when considering the use of Southern blot analysis for families wi th breast/ovarian cancer who do not have detectable coding-region mutations .