Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
- PMID: 25741868
- PMCID: PMC4544753
- DOI: 10.1038/gim.2015.30
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Abstract
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes, and epigenetic assays for genetic disorders. By virtue of increased complexity, this shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context the ACMG convened a workgroup in 2013 comprising representatives from the ACMG, the Association for Molecular Pathology (AMP), and the College of American Pathologists to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP, and College of American Pathologists stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. This report recommends the use of specific standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified in genes that cause Mendelian disorders. Moreover, this recommendation describes a process for classifying variants into these five categories based on criteria using typical types of variant evidence (e.g., population data, computational data, functional data, segregation data). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments-approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
Conflict of interest statement
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Comment in
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Genetic testing. ACMG guides on the interpretation of sequence variants.Nat Rev Genet. 2015 May;16(5):256-7. doi: 10.1038/nrg3940. Epub 2015 Apr 9. Nat Rev Genet. 2015. PMID: 25854183 No abstract available.
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Interpreting sequence variants in a clinical context.Genet Med. 2015 Dec;17(12):1012. doi: 10.1038/gim.2015.150. Epub 2015 Nov 5. Genet Med. 2015. PMID: 26540153 No abstract available.
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Response to Cederbaum.Genet Med. 2015 Dec;17(12):1013-4. doi: 10.1038/gim.2015.151. Epub 2015 Nov 12. Genet Med. 2015. PMID: 26562226 No abstract available.
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The ACMG/AMP reputable source criteria for the interpretation of sequence variants.Genet Med. 2018 Dec;20(12):1687-1688. doi: 10.1038/gim.2018.42. Genet Med. 2018. PMID: 29543229 Free PMC article. No abstract available.
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Response to Biesecker and Harrison.Genet Med. 2018 Dec;20(12):1689-1690. doi: 10.1038/gim.2018.43. Genet Med. 2018. PMID: 29543230 No abstract available.
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A survey assessing adoption of the ACMG-AMP guidelines for interpreting sequence variants and identification of areas for continued improvement.Genet Med. 2019 Aug;21(8):1699-1701. doi: 10.1038/s41436-018-0432-7. Epub 2019 Jan 23. Genet Med. 2019. PMID: 30670879 Free PMC article. No abstract available.
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Comment on the criteria for interpretation of mitochondrial tRNA variants.Genet Med. 2020 Aug;22(8):1418-1419. doi: 10.1038/s41436-020-0804-7. Epub 2020 May 18. Genet Med. 2020. PMID: 32418987 No abstract available.
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Correspondence on "The role of clinical response to treatment in determining pathogenicity of genomic variants" by Shen et al.Genet Med. 2021 Mar;23(3):586. doi: 10.1038/s41436-020-01032-6. Epub 2020 Nov 6. Genet Med. 2021. PMID: 33154565 No abstract available.
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