Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation


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Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80–90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for


germline mutations in BRCA1. Twenty–two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the


location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3′ third of the


gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have


found at least two examples where recurrent mutations appear to have arisen independently.


Simon A. Gayther, William Warren and Sylvie Mazoyer: These authors contributed equally to the study.


CRC Human Cancer Genetics Research Group, Addenbrooke's Hospital, Box 238, Hills Road, Cambridge, CB2 2QQ, UK


Simon A. Gayther, Sylvie Mazoyer, Paul A. Russell, Patricia A. Harrington, Mathias Chiano, Elizabeth J. van Rensburg, Alison M. Dunning & Bruce A.J. Ponder


Section of Molecular Carcinogenesis, Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK


William Warren, Sheila Seal, Rifat Hamoudi & Michael R. Stratton


MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge, CB2 2SR, UK


Department of Human Genetics, University of Pretoria, P.O. Box 2034, Pretoria, 0001, South Africa


Cancer Prevention Programme, 1300 University Avenue, 7C, Madison, Wisconsin, 53706, USA


Regional Genetics Service, St. Mary's Hospital Manchester, Whitworth Park, Manchester, M13 OJH, UK


Department of Community Medicine, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge, CB2 2SR, UK


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