TY - JOUR
T1 - The Clinical Variant Analysis Tool
T2 - Analyzing the evidence supporting reported genomic variation in clinical practice
AU - Chin, Hui Lin
AU - Gazzaz, Nour
AU - Huynh, Stephanie
AU - Handra, Iulia
AU - Warnock, Lynn
AU - Moller-Hansen, Ashley
AU - Boerkoel, Pierre
AU - Jacobsen, Julius O.B.
AU - du Souich, Christèle
AU - Zhang, Nan
AU - Shefchek, Kent
AU - Prentice, Leah M.
AU - Washington, Nicole
AU - Haendel, Melissa
AU - Armstrong, Linlea
AU - Clarke, Lorne
AU - Li, Wenhui Laura
AU - Smedley, Damian
AU - Robinson, Peter N.
AU - Boerkoel, Cornelius F.
N1 - Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - Exome sequencing
KW - Genomic medicine
KW - Precision medicine
KW - Variant classification
KW - Variant interpretation
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U2 - 10.1016/j.gim.2022.03.013
DO - 10.1016/j.gim.2022.03.013
M3 - Article
C2 - 35442193
AN - SCOPUS:85129118449
SN - 1098-3600
VL - 24
SP - 1512
EP - 1522
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -