Although more than 100 different BRCA1 germ-line mutations have already been identified in breast and/or ovarian cancer families, we report for the first time a deleterious genomic rearrangement in BRCA1. A 1-kb deletion comprising exon 17 was found in a large breast and ovarian cancer family, leading to a frameshift in the mutant mRNA due to the absence of exon 17. This deletion is probably the result of a recombination between two closely related Alu sequences. It was not detected by conventional PCR-based methods involving the genomic screening of the 22 coding exons or reverse transcription-PCR because the transcript without exon 17 is unstable in lymphoblastoid cell lines. Therefore, rearrangements in the BRCA1 gene should be sought in breast/ovarian cancer families in which no mutations have been found by PCR-based methods in the coding region or in the splice sites.
Supported by program grants from le Comité Départemental de l'Ain de La Ligue Nationale contre le Cancer, the Council for Tobacco Research (Grant 127DR@), the Department of the United States Army (Grant DAMD17-94-J-4340), and the Nebraska State Cancer and Smoking-related Diseases Program. N. P. is a fellow of the Ligue contre le Cancer de Haute-Savoie, and S. M. is a recipient of an IARC special training award.