BRCA1 sequence analysis in women at high risk for susceptibility mutations: Risk factor analysis and implications for genetic testing

Donna Shattuck-Eidens, Arnold Oliphant, Melody McClure, Celeste McBride, Jamila Gupte, Todd Rubano, Dmitry Pruss, Sean V. Tavtigian, David H.F. Teng, Nils Adey, Mark Staebell, Kathryn Gumpper, Ron Lundstrom, Mark Hulick, Mark Kelly, John Holmen, Beth Lingenfelter, Susan Manley, Frank Fujimura, Michael LuceBrian Ward, Lisa Cannon-Albright, Linda Steele, Kenneth Offit, Teresa Gilewski, Larry Norton, Karen Brown, Charlene Schulz, Heather Hampel, Alice Schluger, Elena Giulotto, Wainer Zoli, Alberto Ravaioli, Heli Nevanlinna, Seppo Pyrhonen, Peter Rowley, Starlene Loader, Michael P. Osborne, Mary Daly, Isidore Tepler, Paul L. Weinstein, Jennifer L. Scalia, Richard Michaelson, Rodney J. Scott, Paolo Radice, Marco A. Pierotti, Judy E. Garber, Claudine Isaacs, Beth Peshkin, Marc E. Lippman, Michael H. Dosik, Maria A. Caligo, Robert M. Greenstein, Robert Pilarski, Barbara Weber, Renate Burgemeister, Thomas S. Frank, Mark H. Skolnick, Alun Thomas

Research output: Contribution to journalArticlepeer-review

347 Scopus citations


Context. - A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete. Objectives. - To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer. Design. - A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland. Participants. - Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus. Major Outcome Measures. - Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations. Results. - In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer; with or without ovarian cancer), early age at diagnosis. Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation. Conclusions. - Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice.

Original languageEnglish
Pages (from-to)1242-1250
Number of pages9
JournalJAMA - Journal of the American Medical Association
Issue number15
StatePublished - 15 Oct 1997
Externally publishedYes


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