Characterization of BRCA1 and BRCA2 Deleterious Mutations and Variants of Unknown Clinical Significance in Unilateral and Bilateral Breast Cancer: The WECARE Study

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; WECARE Study Collaborative Group

doi:10.1002/humu.21202

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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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Characterization of BRCA1 and BRCA2 Deleterious Mutations and Variants of Unknown Clinical Significance in Unilateral and Bilateral Breast Cancer: The WECARE Study

Åke Borg, Robert W Haile, Kathleen E Malone, Marinela Capanu, Ahn Diep, Therese Törngren, Sharon Teraoka, Colin B Begg, Duncan C Thomas, Patrick Concannon, …

Human mutation, Vol.31(3), pp.E1200-E1240

03/2010

DOI: 10.1002/humu.21202

PMCID: PMC2928257

PMID: 20104584

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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.

Breast Cancer

BRCA1

BRCA2

contralateral

deleterious mutation

risk

unclassified variants

Details

Title: Subtitle: Characterization of BRCA1 and BRCA2 Deleterious Mutations and Variants of Unknown Clinical Significance in Unilateral and Bilateral Breast Cancer: The WECARE Study
Creators: Åke Borg - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Robert W Haile - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Kathleen E Malone - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Marinela Capanu - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Ahn Diep - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Therese Törngren - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Sharon Teraoka - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Colin B Begg - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Duncan C Thomas - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Patrick Concannon - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Lene Mellemkjaer - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Leslie Bernstein - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Lina Tellhed - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Shanyan Xue - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Eric R Olson - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Xiaolin Liang - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Jessica Dolle - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Anne-Lise Børresen-Dale - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
Jonine L Bernstein - Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Department of Population Sciences, Division of Cancer Etiology, City of Hope National Medical Center, Duarte CA USA Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA Departments of Genetics and Medicine, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway; Faculty division The Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Norway
WECARE Study Collaborative Group
Contributors: Charles F Lynch (Contributor) - University of Iowa, Epidemiology
Resource Type: Journal article
Publication Details: Human mutation, Vol.31(3), pp.E1200-E1240
DOI: 10.1002/humu.21202
PMID: 20104584
PMCID: PMC2928257
ISSN: 1059-7794
eISSN: 1098-1004
Language: English
Date published: 03/2010
Academic Unit: Epidemiology
Record Identifier: 9984214711402771

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