Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study |
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| Authors: | Åke Borg Robert W Haile Kathleen E Malone Marinela Capanu Ahn Diep Therese Törngren Sharon Teraoka Colin B Begg Duncan C Thomas Patrick Concannon Lene Mellemkjaer Leslie Bernstein Lina Tellhed Shanyan Xue Eric R Olson Xiaolin Liang Jessica Dolle Anne‐Lise Børresen‐Dale Jonine L Bernstein |
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| Institution: | 1. Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden;2. Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA;3. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;4. Department of Epidemiology and Biostatistics, Memorial Sloan‐Kettering Cancer Center, New York, NY, USA;5. Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA;6. Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark;7. Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA;8. Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA;9. Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway |
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| Abstract: | BRCA1 and BRCA2 screening in women at high‐risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population‐based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA‐binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. © 2010 Wiley‐Liss, Inc. |
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| Keywords: | Breast cancer BRCA1 BRCA2 contralateral risk deleterious mutation unclassified variants |
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