To date, more than 300 distinct small deletions, insertions and point mutations, mostly leading to premature termination of translation1, have been reported in the breast/ovarian-cancer susceptibility gene BRCA1. The elevated frequencies of some mutations in certain ethnic subpopulations2–4 are caused by founder effects5,6, rather than by mutation hotspots. Here we report that the currently available mutation spectrum of BRCA1 has been biased by PCR-based mutation-screening methods, such as SSCP, the protein truncation test (PTT) and direct sequencing, using genomic DMA as template. Three large genomic deletions that are not detected by these approaches comprise 36% of all BRCA1 mutations found in Dutch breast-cancer families to date. A 510-bp Alu-mediated deletion comprising exon 22 was found in 8 of 170 breast-cancer families recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counselling. In addition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detected in 6 of the 170 research families, while an deletion of approximately 14 kb was detected in a single family. Haplotype analyses indicated that each recurrent deletion had a single common ancestor.

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  1. Department of Human Genetics, Leiden University Medical Centre, P.O. Box 9600,2300 RA Leiden, The Netherlands.

    • Anne Petrij-Bosch
    • , Tamara Peelen
    • , Margreethe van Vliet
    • , Renske Olmer
    • , Marion Drüsedau
    • , Egbert Bakker
    • , Gert-Jan B. van Ommen
    •  & Peter Devilee
  2. Department of Pathology, Leiden University Medical Centre, P.O. Box 9600,2300 RA Leiden, The Netherlands.

    • Ronald van Eijk
    • , Cees J. Cornelisse
    •  & Peter Devilee
  3. Department of Pathology and Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

    • Frans B.L. Hogervorst
    • , Sandra Hageman
    •  & Laura J. van't Veer
  4. Department of Human Genetics, University Hospital, Nijmegen, The Netherlands.

    • Petronella J.W. Arts
    •  & Marjolijn J.L. Ligtenberg
  5. Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.

    • Hanne Meijers-Heijboer
  6. Daniël den Hoed Cancer Centre and Family Cancer Clinic, Rotterdam, The Netherlands.

    • Jan G.M. Klijn
  7. Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands.

    • Hans R.A. Vasen


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