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Research Brief

Biallelic Deleterious BRCA1 Mutations in a Woman with Early-Onset Ovarian Cancer

Susan M. Domchek, Jiangbo Tang, Jill Stopfer, Dana R. Lilli, Nancy Hamel, Marc Tischkowitz, Alvaro N.A. Monteiro, Troy E. Messick, Jacquelyn Powers, Alexandria Yonker, Fergus J. Couch, David E. Goldgar, H. Rosemarie Davidson, Katherine L. Nathanson, William D. Foulkes and Roger A. Greenberg
Susan M. Domchek
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Jiangbo Tang
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Jill Stopfer
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Dana R. Lilli
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Nancy Hamel
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Marc Tischkowitz
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Alvaro N.A. Monteiro
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Troy E. Messick
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Jacquelyn Powers
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Alexandria Yonker
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Fergus J. Couch
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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David E. Goldgar
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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H. Rosemarie Davidson
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Katherine L. Nathanson
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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William D. Foulkes
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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Roger A. Greenberg
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
1Abramson Cancer Center, Departments of 2Medicine, 3Cancer Biology, and 4Pathology and Laboratory Medicine, 5Basser Research Center for BRCA1/2, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; 6Vironika, Philadelphia, Pennsylvania; 7Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital; 8Program in Cancer Genetics, Departments of Oncology and Human Genetics, and 9Research Institute, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 10Department of Medical Genetics, University of Cambridge, Cambridge; and 11Ferguson Smith Centre for Clinical Genetics, Yorkhill, Glasgow, United Kingdom; 12Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida; 13Cancer Genetic Risk Assessment Program, Bryan Hemming Cancer Care Center, San Francisco, California; 14Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 15Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
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DOI: 10.1158/2159-8290.CD-12-0421 Published April 2013
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Abstract

BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results.

Significance: Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the first validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy. Cancer Discov; 3(4); 399–405. ©2012 AACR.

See related commentary by D'Andrea, p. 376

This article is highlighted in the In This Issue feature, p. 363

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received September 18, 2012.
  • Revision received December 16, 2012.
  • Accepted December 21, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Discovery: 3 (4)
April 2013
Volume 3, Issue 4
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Biallelic Deleterious BRCA1 Mutations in a Woman with Early-Onset Ovarian Cancer
Susan M. Domchek, Jiangbo Tang, Jill Stopfer, Dana R. Lilli, Nancy Hamel, Marc Tischkowitz, Alvaro N.A. Monteiro, Troy E. Messick, Jacquelyn Powers, Alexandria Yonker, Fergus J. Couch, David E. Goldgar, H. Rosemarie Davidson, Katherine L. Nathanson, William D. Foulkes and Roger A. Greenberg
Cancer Discov April 1 2013 (3) (4) 399-405; DOI: 10.1158/2159-8290.CD-12-0421

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Biallelic Deleterious BRCA1 Mutations in a Woman with Early-Onset Ovarian Cancer
Susan M. Domchek, Jiangbo Tang, Jill Stopfer, Dana R. Lilli, Nancy Hamel, Marc Tischkowitz, Alvaro N.A. Monteiro, Troy E. Messick, Jacquelyn Powers, Alexandria Yonker, Fergus J. Couch, David E. Goldgar, H. Rosemarie Davidson, Katherine L. Nathanson, William D. Foulkes and Roger A. Greenberg
Cancer Discov April 1 2013 (3) (4) 399-405; DOI: 10.1158/2159-8290.CD-12-0421
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