Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions

Most previous BRCA1 mutation screening studies conducted on breast cancer f amilies were aimed at identifying mutations in the coding sequence and spli ce sites. Mutations in the promoter and untranslated regions, and large rea rrangements are missed by standard mutation detection strategies. To look s pecifically for such germ-line mutations in the BRCA1 gene, we have analyze d a series of 27 American and 51 French breast cancer families in which no BRCA1 mutation was identified by classical techniques. No mutations were de tected in either the promoter or untranslated regions, and we did not End a ny deletion of the whole gene. Four families were found to carry distinct d eletions. Two of them, probably generated by Alu-mediated homologous recomb ination, were internal deletions of 3 and 23.8 kb, encompassing exon 15 and exons 8-13, respectively. These alterations both lead to a frameshift in t he mutant mRNA and to premature stop codon-mediated mRNA decay, The other t wo deletions encompass exons I and 2, On the basis of previous and present analyses, rearrangements represent 8% (3/37) of all mutations in our set of BRCA1 American families. Consequently, the search for rearrangements appea rs mandatory in BRCA1 mutation screening studies.