Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel
Abstract
Abstract The ENIGMA research consortium ( https://enigmaconsortium.org/ ) develops and applies methods to determine clinical significance of variants in Hereditary Breast and Ovarian Cancer genes. An ENIGMA BRCA1/2 classification sub-group, originally formed in 2016 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Federal Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics/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 both the research processes and the baseline ACMG/AMP criteria. Calibration of evidence types was key to justify utility and strength of different evidence types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.
Authors 42
-
QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
-
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 Clínico San Carlos, IdISSC, 8040 Madrid, Spain
-
Ambry Genetics (United States)
Affiliation as printed
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA
-
QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
-
Affiliation as printed
GeneDx, Gaithersburg, Maryland, USA
-
Université Paris Sciences et Lettres · Institut Curie
Affiliation as printed
Department of Genetics, Institut Curie, 75005 Paris, France and Paris Sciences Lettres Research University, Paris, 75005, France
-
Affiliation as printed
Color Health, Burlingame, CA, USA
-
University of California, Santa Cruz
Affiliation as printed
UC Santa Cruz Genomics Institute, Mail Stop: Genomics, University of California, 1156 High Street, Santa Cruz, CA, 95064, USA
-
University of Utah · Huntsman Cancer Institute
Affiliation as printed
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
-
QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
-
Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
-
QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
-
Affiliation as printed
GeneDx, Gaithersburg, Maryland, USA
-
Affiliation as printed
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
-
Inserm · Université de Rouen Normandie
Affiliation as printed
Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, FHU G4 génomique F-76000 Rouen, France
Univ Rouen Normandie, Inserm U45 and CHU Rouen, Department of Genetics, FHU G4 génomique F-76000 Rouen, France
-
Affiliation as printed
GeneDx, Gaithersburg, Maryland, USA
-
Affiliation as printed
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
-
Ambry Genetics (United States)
Affiliation as printed
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA
-
Affiliation as printed
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia
-
Inserm · Université de Rouen Normandie
Affiliation as printed
Univ Rouen Normandie, Inserm U1245, F-76000 Rouen, France
-
Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands
-
Affiliation as printed
Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
-
QIMR Berghofer Medical Research Institute
Affiliation as printed
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
-
Affiliation as printed
Color Health, Burlingame, CA, USA
-
Aalborg University Hospital · Aalborg University
Affiliation as printed
Clinical Cancer Research Center, Aalborg University Hospital, Denmark
Dept. of Clinical Medicine, Aalborg University, Denmark
Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark
-
Ambry Genetics (United States)
Affiliation as printed
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA
-
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
-
Medizinische Hochschule Hannover
Affiliation as printed
Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany
-
The University of Melbourne · Cancer Council Victoria · Monash Health · Monash University
Affiliation as printed
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VC, Australia
Department of Clinical Pathology, The Melbourne Medicial School, The University of Melbourne, Victoria, 3010, Australia
Precision Medicine, School of Clinial Sciencs at Monash Health, Monash University, Clayton, Victoria, 3168, Australia
-
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
-
Affiliation as printed
Department of Pathology, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia
-
Affiliation as printed
Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
-
Affiliation as printed
Translational Genetics Team, Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
-
Amsterdam University Medical Centers
Affiliation as printed
Department of Human Genetics, Amsterdam University Medical Centers, Amsterdam, The Netherlands
-
Ambry Genetics (United States)
Affiliation as printed
Ambry Genetics Corporation, Aliso Viejo, CA 92656, USA
-
Affiliation as printed
Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
-
Affiliation as printed
Natera, Inc, San Carlos, CA, USA
-
Affiliation as printed
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
-
Affiliation as printed
Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
-
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
-
University of Utah · Huntsman Cancer Institute
Affiliation as printed
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
-
Amanda B. Spurdle corresponding
The University of Queensland · QIMR Berghofer Medical Research Institute
Affiliation as printed
Faculty of Medicine, University of Queensland, Australia
Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
Cited by 5 stored of 6
5 results
No patents citing this paper on Lens.org (checked 2026-10-11).