Hui-Lin Chin1, Nour Gazzaz2, Stephanie Huynh3, Iulia Handra3, Lynn Warnock4, Ashley Moller-Hansen4, Pierre Boerkoel5, Julius O B Jacobsen6, Christèle du Souich7, Nan Zhang8, Kent Shefchek9, Leah M Prentice10, Nicole Washington11, Melissa Haendel9, Linlea Armstrong3, Lorne Clarke3, Wenhui Laura Li8, Damian Smedley6, Peter N Robinson12, Cornelius F Boerkoel13. 1. Department of Medical Genetics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada; Provincial Medical Genetics Program, Women's Hospital of British Columbia, Vancouver, British Columbia, Canada; Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore, Singapore. 2. Department of Medical Genetics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada; Provincial Medical Genetics Program, Women's Hospital of British Columbia, Vancouver, British Columbia, Canada; Department of Pediatrics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada; Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. 3. Department of Medical Genetics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada; Provincial Medical Genetics Program, Women's Hospital of British Columbia, Vancouver, British Columbia, Canada. 4. Provincial Medical Genetics Program, Women's Hospital of British Columbia, Vancouver, British Columbia, Canada. 5. MD Undergraduate Program, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 6. William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom. 7. Department of Medical Genetics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. 8. Breakthrough Genomics, Irvine, CA. 9. Oregon Clinical and Translational Science Institute, Oregon Health & Science University, Portland, OR. 10. Provincial Laboratory Medicine Services, Provincial Health Services Authority, Vancouver, British Columbia, Canada. 11. Helix, San Mateo, CA. 12. Jackson Laboratory for Genomic Medicine, Farmington, CT. 13. Department of Medical Genetics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada; Provincial Medical Genetics Program, Women's Hospital of British Columbia, Vancouver, British Columbia, Canada. Electronic address: cboerkoel@gmail.com.
Abstract
PURPOSE: Genomic test results, regardless of laboratory variant classification, require clinical practitioners to judge the applicability of a variant for medical decisions. Teaching and standardizing clinical interpretation of genomic variation calls for a methodology or tool. METHODS: To generate such a tool, we distilled the Clinical Genome Resource framework of causality and the American College of Medical Genetics/Association of Molecular Pathology and Quest Diagnostic Laboratory scoring of variant deleteriousness into the Clinical Variant Analysis Tool (CVAT). Applying this to 289 clinical exome reports, we compared the performance of junior practitioners with that of experienced medical geneticists and assessed the utility of reported variants. RESULTS: CVAT enabled performance comparable to that of experienced medical geneticists. In total, 124 of 289 (42.9%) exome reports and 146 of 382 (38.2%) reported variants supported a diagnosis. Overall, 10.5% (1 pathogenic [P] or likely pathogenic [LP] variant and 39 variants of uncertain significance [VUS]) of variants were reported in genes without established disease association; 20.2% (23 P/LP and 54 VUS) were in genes without sufficient phenotypic concordance; 7.3% (15 P/LP and 13 VUS) conflicted with the known molecular disease mechanism; and 24% (91 VUS) had insufficient evidence for deleteriousness. CONCLUSION: Implementation of CVAT standardized clinical interpretation of genomic variation and emphasized the need for collaborative and transparent reporting of genomic variation.
PURPOSE: Genomic test results, regardless of laboratory variant classification, require clinical practitioners to judge the applicability of a variant for medical decisions. Teaching and standardizing clinical interpretation of genomic variation calls for a methodology or tool. METHODS: To generate such a tool, we distilled the Clinical Genome Resource framework of causality and the American College of Medical Genetics/Association of Molecular Pathology and Quest Diagnostic Laboratory scoring of variant deleteriousness into the Clinical Variant Analysis Tool (CVAT). Applying this to 289 clinical exome reports, we compared the performance of junior practitioners with that of experienced medical geneticists and assessed the utility of reported variants. RESULTS: CVAT enabled performance comparable to that of experienced medical geneticists. In total, 124 of 289 (42.9%) exome reports and 146 of 382 (38.2%) reported variants supported a diagnosis. Overall, 10.5% (1 pathogenic [P] or likely pathogenic [LP] variant and 39 variants of uncertain significance [VUS]) of variants were reported in genes without established disease association; 20.2% (23 P/LP and 54 VUS) were in genes without sufficient phenotypic concordance; 7.3% (15 P/LP and 13 VUS) conflicted with the known molecular disease mechanism; and 24% (91 VUS) had insufficient evidence for deleteriousness. CONCLUSION: Implementation of CVAT standardized clinical interpretation of genomic variation and emphasized the need for collaborative and transparent reporting of genomic variation.
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