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Implications for Presymptomatic Testing and Screening

Donna Shattuck-Eidens, PhD; Melody McClure; Jacques Simard, PhD; Fernand Labrie, MD, PhD; Steve Narod, MD; Fergus Couch, PhD; Kent Hoskins, MD; Barbara Weber, MD; Lucio Castilla, PhD; Mike Erdos; Lawrence Brody, PhD; Lori Friedman; Elizabeth Ostermeyer; Csilla Szabo, PhD; Mary-Claire King, PhD; Suresh Jhanwar, PhD; Kenneth Offit, MD; Larry Norton, MD; Teresa Gilewski, MD; Mathew Lubin, MD; Michael Osborne, MD; Donald Black, PhD; Marie Boyd; Michael Steel, MD; Sue Ingles; Robert Haile, PhD; Annika Lindblom, MD; Hakan Olsson, MD, PhD; Ake Borg, PhD; D. Timothy Bishop, PhD; Ellen Solomon, PhD; Paolo Radice, MD; Giovanbattista Spatti, MD; Simon Gayther, PhD; Bruce Ponder, MD, PhD; William Warren; Mike Stratton, MD, PhD; Qingyun Liu, PhD; Frank Fujimura, PhD; Cathryn Lewis, PhD; Mark H. Skolnick, PhD; David E. Goldgar, PhD

JAMA. 1995;273(7):535-541.

Abstract
Objectives.
—To report the initial experience of an international group of investigators in identifying mutations in the BRCA1 breast and ovarian cancer susceptibility gene, to assess the spectrum of such mutations in samples from patients with different family histories of cancer, and to determine the frequency of recurrent mutations.

Design.
—Nine laboratories in North America and the United Kingdom tested for BRCA 1 mutations in DNA samples obtained from a total of 372 unrelated patients with breast or ovarian cancer largely chosen from high-risk families. Three of these laboratories also analyzed a total of 714 additional samples from breast or ovarian cancer cases, including 557 unselected for family history, for two specific mutations that had been found to recur in familial samples.

Participants.
—A total of 1086 women with either breast or ovarian cancer.

Main Outcome Measure.
—The detection of sequence variation in patients' DNA samples that is not found in sets of control samples.

Results.
—BRCA 1 mutations have now been identified in a total of 80 patient samples. Thirty-eight distinct mutations were found among 63 mutations identified through a complete screen of the BRCA 1 gene. Three specific mutations appeared relatively common, occurring eight, seven, and five times, respectively. When specific tests for the two most common mutations were performed in larger sets of samples, they were found in 17 additional patients. Mutations predicted to result in a truncated protein accounted for 86% of the mutations detected by complete screening.

Conclusions.
—The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test for BRCA 1 mutations. More data must be accumulated to address specifically the sensitivity and specificity of such a diagnostic testing procedure and to better estimate the age-specific risk for breast and ovarian cancer associated with such mutations.

(JAMA. 1995;273:535-541)

Footnotes
A complete list of author affiliations appears at the end of this article. Drs Skolnick, Lewis, and Goldgar have stock options in Myriad Genetics, which may offer diagnostic testing for BRCA1 in the future. Dr Skolnick is vice president of Myriad Genetics.

Reprint requests to Department of Medical Informatics, University of Utah School of Medicine, 391 Chipeta Way, Suite D2, Salt Lake City, UT 84108 (Dr Goldgar).

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