Rates and Classification of Variants of Uncertain Significance in Hereditary Disease Genetic Testing

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dc.contributor.authorChen, Elaine
dc.contributor.authorFacio, Flavia M.
dc.contributor.authorAradhya, Kerry W.
dc.contributor.authorRojahn, Susan
dc.contributor.authorHatchell, Kathryn E.
dc.contributor.authorAguilar, Sienna
dc.contributor.authorOuyang, Karen
dc.contributor.authorSaitta, Sulagna
dc.contributor.authorHanson-Kwan, Andrea K.
dc.contributor.authorCapurro, Nicole Nakousi
dc.contributor.authorTakamine, Eriko
dc.contributor.authorJamuar, Saumya Shekhar
dc.contributor.authorMcKnight, Dianalee
dc.contributor.authorJohnson, Britt
dc.contributor.authorAradhya, Swaroop
dc.date.accessioned2025-01-28T14:31:52Z
dc.date.available2025-01-28T14:31:52Z
dc.date.issued2023-10
dc.descriptionIndexación: Scopus
dc.description.abstractImportance: Variants of uncertain significance (VUSs) are rampant in clinical genetic testing, frustrating clinicians, patients, and laboratories because the uncertainty hinders diagnoses and clinical management. A comprehensive assessment of VUSs across many disease genes is needed to guide efforts to reduce uncertainty. Objective: To describe the sources, gene distribution, and population-level attributes of VUSs and to evaluate the impact of the different types of evidence used to reclassify them. Design, Setting, and Participants: This cohort study used germline DNA variant data from individuals referred by clinicians for diagnostic genetic testing for hereditary disorders. Participants included individuals for whom gene panel testing was conducted between September 9, 2014, and September 7, 2022. Data were analyzed from September 1, 2022, to April 1, 2023. Main Outcomes and Measures: The outcomes of interest were VUS rates (stratified by age; clinician-reported race, ethnicity, and ancestry groups; types of gene panels; and variant attributes), percentage of VUSs reclassified as benign or likely benign vs pathogenic or likely pathogenic, and enrichment of evidence types used for reclassifying VUSs. Results: The study cohort included 1689845 individuals ranging in age from 0 to 89 years at time of testing (median age, 50 years), with 1203210 (71.2%) female individuals. There were 39150 Ashkenazi Jewish individuals (2.3%), 64730 Asian individuals (3.8%), 126739 Black individuals (7.5%), 5539 French Canadian individuals (0.3%), 169714 Hispanic individuals (10.0%), 5058 Native American individuals (0.3%), 2696 Pacific Islander individuals (0.2%), 4842 Sephardic Jewish individuals (0.3%), and 974383 White individuals (57.7%). Among all individuals tested, 692227 (41.0%) had at least 1 VUS and 535385 (31.7%) had only VUS results. The number of VUSs per individual increased as more genes were tested, and most VUSs were missense changes (86.6%). More VUSs were observed per sequenced gene in individuals who were not from a European White population, in middle-aged and older adults, and in individuals who underwent testing for disorders with incomplete penetrance. Of 37699 unique VUSs that were reclassified, 30239 (80.2%) were ultimately categorized as benign or likely benign. A mean (SD) of 30.7 (20.0) months elapsed for VUSs to be reclassified to benign or likely benign, and a mean (SD) of 22.4 (18.9) months elapsed for VUSs to be reclassified to pathogenic or likely pathogenic. Clinical evidence contributed most to reclassification. Conclusions and Relevance: This cohort study of approximately 1.6 million individuals highlighted the need for better methods for interpreting missense variants, increased availability of clinical and experimental evidence for variant classification, and more diverse representation of race, ethnicity, and ancestry groups in genomic databases. Data from this study could provide a sound basis for understanding the sources and resolution of VUSs and navigating appropriate next steps in patient care. © 2023 American Medical Association. All rights reserved.
dc.description.urihttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2810999
dc.identifier.citationJAMA Network Open. Volume 6, Issue 10, Pages E2339571. 25 October 2023
dc.identifier.doi10.1001/jamanetworkopen.2023.39571
dc.identifier.issn2574-3805
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/63320
dc.language.isoen
dc.publisherAmerican Medical Association
dc.rights.licenseCC-BY-NC-ND License
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subjectAdolescent
dc.subjectAdult
dc.subjectGenetic Testing
dc.subjectVariants of Uncertain Significance (VUSs)
dc.subjectEthnicity
dc.subjectFemale
dc.subjectAmerican Indian or Alaska Native
dc.subjectCohort Studies
dc.titleRates and Classification of Variants of Uncertain Significance in Hereditary Disease Genetic Testing
dc.typeArtículo
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