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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Couch, F.J. et al. Mutations and polymorphisms in the familial early onset breast cancer (BRCA1). gene. Hum. Mutat. 8, 8–18 (1996).
Roa, B.B., Boyd, A.A., Volcik, K. & Richards, C.S., Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nature Genet. 14, 185–187 (1996).
Caligo, M.A. et al. BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations. Oncogene. 13, 1483–1488 (1996).
Peelen, T. et al. A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am. J. Hum. Genet. 60, 1041–1049 (1997).
Neuhausen, S.L. et al. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am. J. Hum. Genet. 58, 271–280 (1996).
Szabo, C.I. & King, M.-C. Population genetics of BRCA1 and BRCA2. Am. J. Hum. Genet. 60, 1013–1020 (1997).
Hogervorst, F.B.L. et al. Rapid detection of BRCA1 mutations by the protein truncation test. Nature Genet. 10, 208–212 (1995).
Peelen, T. et al. The majority of 22 Dutch high-risk breast cancer families are due to either BRCA1 or BRCA2. Eur. J. Hum. Genet. 4, 225–230 (1996).
Shapiro, M.B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155–7174 (1997).
Smith, T.M. et al. Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1. Genome Res. 6, 1029–1049 (1996).
Rudiger, N.S., Gregersen, N. & Kielland-Brandt, M.C. One short well conserved region of Alu-sequences is involved in human gene rearrangements and has homology with prokaryotic chi. Nucleic Acids Res. 23, 256–260 (1995).
Puget, N. et al. A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res. 57, 828–831 (1997).
Szabo, C.I. & King, M.-C. Inherited breast and ovarian cancer. Hum. Mol. Genet. 4, 1811–1817 (1995).
Futreal, P.A. et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 266, 120–122 (1994).
Katagiri, T. et al. Mutations in the BRCA1 gene in Japanese breast cancer patients. Hum. Mutat. 7, 334–339 (1996).
Easton, D., Bishop, D., Ford, D., Crockford, G. & & the Breast Cancer Linkage Consortium. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am. J. Hum. Genet. 52, 678–701 (1993).
Narod, S. et al. An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am. J. Hum. Genet. 56, 254–264 (1995).
Cast ilia, L . et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nature Genet. 8, 387–391 (1994).
Inoue, R. et al. Germline mutation of BRCA1 in Japanese breast cancer families. Cancer Res. 55, 3521–3524 (1995).
Durocher, F. et al. Mutation analysis of the BRCA1 gene in 23 families with cases of cancer of the breast, ovary, and multiple other sites. J. Med. Genet. 33, 814–819 (1996).
Xu, C.F. et al. Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families. Genes Chrom. Cancer. 18, 102–110 (1997).
Hamann, U., Brauch, H., Garvin, A.M., Bastert, G. & Scott, R.J. German family study on hereditary breast and/or ovarian cancer: germline mutation analysis of the BRCA1 gene. Genes Chrom. Cancer. 18, 126–132 (1997).
Shattuck-Eidens, D. et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene: implications for presymptomatic testing and screening. JAMA 273, 535–541 (1995).
Devilee, P. et al. At least four different chromosomal regions are involved in loss of heterozygosity in human breast carcinoma. Genomics. 5, 554–560 (1989).
Friedman, L. et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nature Genet. 8, 399–404 (1994).
About this article
The EMBO Journal (2019)
Mexican BRCA1 founder mutation: Shortening the gap in genetic assessment for hereditary breast and ovarian cancer patients
PLOS ONE (2019)
The Journal of Molecular Diagnostics (2018)
Antioxidants & Redox Signaling (2018)
Comprehensive BRCA mutation analysis in the Greek population. Experience from a single clinical diagnostic center
Cancer Genetics (2018)