ArticleAmerican journal of human genetics2020
Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies.
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed.
- Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.European heart journal · 2026Article
- Validation structures for sequence variants of uncertain significance in hereditary cancer.European journal of human genetics : EJHG · 2026Review
- Integration of Machine Learning-Based Pathogenicity Prediction and Phenotype Matching Improves Variant Prioritization in Rare Clinical Testing.Current issues in molecular biology · 2026Article
- Exome sequencing early in outpatient evaluation in NCGENES 2: Changing the course of the diagnostic odyssey?HGG advances · 2026Article
- Elective genomic sequencing for adults in research, clinical and commercial contexts.BMC medical genomics · 2026Article
- Elective genomic sequencing for adults in research, clinical and commercial contexts.medRxiv : the preprint server for health sciences · 2026Article
- Diagnostic Value of Exome Sequencing in Isolated Polyhydramnios.Prenatal diagnosis · 2026Article
- Specification of frequency criteria for secondary findings genes to improve variant classification concordance.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Determinants of DNA-sequence-based Diagnostic Yield in the CSER Consortium.medRxiv : the preprint server for health sciences · 2026Article
- Variant interpretation training for the genomics era: Learning outcomes to inform professional competencies and education.American journal of human genetics · 2026Article
- Subtle cellular phenotypes inform pathological and benign genetic mutants in the Iduronate-2 sulfatase gene.Human molecular genetics · 2026Article
- A methodological framework for real-world performance studies of clinical variant classification platforms at early organizational stages.Frontiers in genetics · 2026Article
- TRACE: A Framework for Integrating Transcript Relevance Into ACMG/AMP Variant Interpretation.Human mutation · 2026Review
- Article
- Novel Genetic Insights into Lateral Temporal Lobe Epilepsy: Findings from Whole Exome Sequencing.Noro psikiyatri arsivi · 2026Article
- Pathogenic variants in affected and unaffected individuals from Indonesian familial cancer: a multigene panel analysis.Scientific reports · 2025Article
- Beyond the Exome: The Role of Noncoding and Regulatory Variants in Monogenic Diseases.Current issues in molecular biology · 2025Review
- Germline Variants in the Immune Response-Related Genes: Possible Modifying Effect on Age-DependentCancers · 2025Article
- The promises and pitfalls of automated variant interpretation: a comprehensive review.Briefings in bioinformatics · 2025Review
- HerediVar and HerediClassify: tools for streamlining genetic variant classification in hereditary breast and ovarian cancer.Human genomics · 2025Article
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
31 authors.
Funding
Abstract
Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIA-accredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore current sources of discordance in classification. Eight laboratories each submitted 20 classified variants in the ACMG secondary finding v.2.0 genes. After removing duplicates, each of the 158 variants was annotated and independently classified by two additional laboratories using the ACMG-AMP guidelines. Overall concordance across three laboratories was assessed and discordant variants were reviewed via teleconference and email. The submitted variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and cardiac (27%) risk genes. Eighty-six (54%) variants reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance that could affect clinical recommendations (P/LP versus VUS/LB/B). 21% and 63% of variants submitted as P and LP, respectively, were discordant with VUS. Of the 54 originally discordant variants that underwent further review, 32 reached agreement, for a post-review concordance rate of 84% (118/140 variants). This project provides an updated estimate of variant concordance, identifies considerations for LP classified variants, and highlights ongoing sources of discordance. Continued and increased sharing of variant classifications and evidence across laboratories, and the ongoing work of ClinGen to provide general as well as gene- and disease-specific guidance, will lead to continued increases in concordance.
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