Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel
The American Journal of Human Genetics, vol. 111, pp. 2044–2058
Abstract
The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.
Authors 43
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Michael T. Parsons corresponding
QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. Electronic address: michael.parsons@qimrberghofer.edu.au
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;
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Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Affiliation as printed
Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC, 28040 Madrid Spain
Molecular Oncology Laboratory, Hospital Clı ´nico San Car-los, IdISSC, 28040 Madrid Spain;
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Ambry Genetics (United States)
Affiliation as printed
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA;
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QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;
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Affiliation as printed
Invitae Corporation, San Francisco, CA, USA
Invitae Corporation, San Francisco, CA, USA;
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Affiliation as printed
GeneDx, Gaithersburg, MD, USA
GeneDx, Gai-thersburg, MD, USA;
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Université Paris Sciences et Lettres · Institut Curie
Affiliation as printed
Department of Genetics, Institut Curie, and Paris Sciences Lettres Research University, 75005 Paris, France
Department of Genetics, Institut Curie, and Paris Sciences Lettres Research University, 75005 Paris, France;
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Affiliation as printed
Color Health, Burlingame, CA, USA
Color Health, Burlin-game, CA, USA;
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University of California, Santa Cruz
Affiliation as printed
UC Santa Cruz Genomics Institute, Genomics, University of California, 1156 High Street, Santa Cruz, CA 95064, USA
UC Santa Cruz Genomics Institute, Genomics, University of California, 1156 High Street, Santa Cruz, CA 95064, USA;
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University of Utah · Huntsman Cancer Institute
Affiliation as printed
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA;
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QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands;
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QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;
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Affiliation as printed
GeneDx, Gaithersburg, MD, USA
GeneDx, Gai-thersburg, MD, USA;
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Affiliation as printed
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;
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Inserm · Université de Rouen Normandie
Affiliation as printed
University Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, FHU G4 Génomique, F-76000 Rouen, France
Uni-versity Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, FHU G4 Ge ´nomique, F-76000 Rouen, France;
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Affiliation as printed
GeneDx, Gaithersburg, MD, USA
GeneDx, Gai-thersburg, MD, USA;
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The University of Melbourne · Peter MacCallum Cancer Centre
Affiliation as printed
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia;
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Ambry Genetics (United States)
Affiliation as printed
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA;
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Affiliation as printed
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia
Department of Pathology, Peter MacCallum Cancer Centre, Mel-bourne, VIC 3052, Australia;
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Inserm · Université de Rouen Normandie
Affiliation as printed
University Rouen Normandie, Inserm U1245, F-76000 Rouen, France
University Rouen Normandie, Inserm U1245, F-76000 Rouen, France;
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Department of Human Genetics, Radboud Univer-sity Medical Center, Nijmegen, the Netherlands;
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Affiliation as printed
Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA;
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QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;
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Affiliation as printed
Color Health, Burlingame, CA, USA
Color Health, Burlin-game, CA, USA;
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Aalborg University Hospital · Aalborg University
Affiliation as printed
Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark;
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark;
Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark;
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Ambry Genetics (United States)
Affiliation as printed
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA;
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Fondazione IRCCS Istituto Nazionale dei Tumori
Affiliation as printed
Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Venezian 1, 20133 Milano, Italy
Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Venezian 1, 20133 Milano, Italy;
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany
Institute of Human Genetics, Hann-over Medical School, 30625 Hannover, Germany;
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The University of Melbourne · Cancer Council Victoria · Monash Health · Monash University
Affiliation as printed
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia; Department of Clinical Pathology, The Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3010, Australia
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia;
Department of Clinical Pathology, The Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3010, Australia;
Precision Med-icine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia;
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University of Utah · Huntsman Cancer Institute
Affiliation as printed
Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA
Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA;
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Affiliation as printed
Department of Pathology, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia
Department of Pathology, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia;
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Affiliation as printed
Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
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Affiliation as printed
Translational Genetics Team, Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
Translational Genetics Team, Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK;
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Amsterdam University Medical Centers
Affiliation as printed
Department of Human Genetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
Department of Human Genetics, Amsterdam University Medical Centers, Amster-dam, the Netherlands;
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Ambry Genetics (United States)
Affiliation as printed
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA;
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Affiliation as printed
Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand;
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Affiliation as printed
Natera, Inc, San Carlos, CA, USA
Natera, Inc, San Carlos, CA, USA;
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Affiliation as printed
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;
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Affiliation as printed
Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand;
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The University of Queensland · Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; 34 Faculty of Medicine, University of Queensland, Bris-bane, QLD, Australia
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University of Utah · Huntsman Cancer Institute
Affiliation as printed
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA;
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Amanda B. Spurdle corresponding
The University of Queensland · University of California, Santa Cruz · QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. Electronic address: amanda.spurdle@qimrberghofer.edu.au
UC Santa Cruz
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