An Alu-mediated 7.1 kb deletion of BRCAI exons 8 and 9 in breast and ovarian cancer families that results in alternative splicing of exon 10

Constitutive large deletions and duplications of BRCA I resulting from Alu- mediated recombination account for a significant proportion of disease-caus ing mutations in breast and/or ovarian cancer families, Using Southern blot analysis and a protein truncation test (PTT), we have identified a 7.1 kb germline deletion in two families with breast and ovarian cancer. This dele tion, which includes exons 8 and 9 and leads to a frameshift at the mRNA le vel, appears to result from homologous recombination between closely relate d Alu repeats, one in intron 7 and one in intron 9. In addition to the tran script without exons 8 and 9, analysis of RNA by protein truncation test fr om individuals with the deletion also identified the presence of alternativ e splicing of exon 10 from the mutant allele, which results in a transcript that lacks exons 8, 9, and 10, Of interest is that the two American famili es who carry this deletion are of northern European ancestry and share a co mmon haplotype, suggesting that this deletion may represent a founder mutat ion. (C) 2000 Wiley-Liss, Inc.