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Guideline

doi: x.1038/gim.2015.30. Epub 2015 Mar v.

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

Nazneen Aziz ^two , Sherri Bale ³ , David Bick ^four , Soma Das ⁵ , Julie Gastier-Foster ⁶ , Wayne West Grody ^vii , Madhuri Hegde ⁸ , Elaine Lyon ⁹ , Elaine Spector ¹⁰ , Karl Voelkerding ⁹ , Heidi L Rehm ¹¹ , ACMG Laboratory Quality Assurance Committee

Affiliations

• PMID: 25741868
• PMCID: PMC4544753
• DOI: 10.1038/gim.2015.30

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Guideline

Standards and guidelines for the estimation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards  et al. Genet Med. 2015 May .

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Abstruse

The American Higher of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing applied science has evolved rapidly with the appearance 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 estimation. In this context the ACMG convened a workgroup in 2013 comprising representatives from the ACMG, the Clan for Molecular Pathology (AMP), and the College of American Pathologists to revisit and revise the standards and guidelines for the estimation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents good opinion of the workgroup with input from ACMG, AMP, and College of American Pathologists stakeholders. These recommendations primarily utilize to the breadth of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. This study recommends the utilise of specific standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "probable beneficial," and "benign"-to draw 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 information, computational data, functional information, segregation data). Because of the increased complexity of analysis and estimation 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 argument

Conflicts of Interest: All workgroup members are clinical service providers. No commercial conflict of interest was reported for Sue Richards, David Bick, Soma Das, Wayne Grody, Elaine Spector, Julie Gastier-Foster, Nazneen Aziz, and Karl Voelkerding. The following workgroup members have a commercial conflict of interest: Sherri Bale (GeneDx, BioReference (stock), Advisory boards for RainDance, Ingenuity); Madhuri Hegde (Advisor for: Oxford Genetic Technologies, Tessarae, Ingenuity/Qiagen); Elaine Lyon (Advisory board for Consummate Genomics); and Heidi Rehm (Scientific informational boards: Ingenuity/Qiagen, Complete Genomics, Knome, Focused Genomics).

Figures

Figure 1. Show Framework

The post-obit chart organizes each of the criteria by the type of evidence as well as the strength of the criteria for a benign (left side) or pathogenic (right side) assertion. Testify code descriptions tin can be found in Tables three and 4. Abbreviations: BS, benign potent; BP, beneficial supporting; FH, family history; LOF, loss-of-function; MAF, small-scale allele frequency; path., pathogenic; PM, pathogenic moderate; PP, pathogenic supporting; PS, pathogenic strong; PVS, pathogenic very stiff

Annotate in

• Genetic testing. ACMG guides on the interpretation of sequence variants.

  Bahcall OG. Bahcall OG. Nat Rev Genet. 2015 May;sixteen(five):256-vii. doi: 10.1038/nrg3940. Epub 2015 Apr 9. Nat Rev Genet. 2015. PMID: 25854183 No abstract available.

• Interpreting sequence variants in a clinical context.

  Cederbaum Southward. Cederbaum S. Genet Med. 2015 Dec;17(12):1012. doi: ten.1038/gim.2015.150. Epub 2015 November 5. Genet Med. 2015. PMID: 26540153 No abstract bachelor.

• Response to Cederbaum.

  Interpretation of Sequence Variants Workgroup. Interpretation of Sequence Variants Workgroup. Genet Med. 2015 December;17(12):1013-4. doi: 10.1038/gim.2015.151. Epub 2015 Nov 12. Genet Med. 2015. PMID: 26562226 No abstruse available.

• The ACMG/AMP reputable source criteria for the interpretation of sequence variants.

  Biesecker LG, Harrison SM; ClinGen Sequence Variant Estimation Working Group. Biesecker LG, et al. Genet Med. 2018 Dec;20(12):1687-1688. doi: ten.1038/gim.2018.42. Genet Med. 2018. PMID: 29543229 Gratis PMC article. No abstruse available.

• Response to Biesecker and Harrison.

  Richards CS, Aziz N, Bale Due south, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde 1000, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG/AMP Interpretation of Sequence Variants Piece of work Group 2015. Richards CS, et al. Genet Med. 2018 Dec;xx(12):1689-1690. doi: 10.1038/gim.2018.43. Genet Med. 2018. PMID: 29543230 No abstract available.

• A survey assessing adoption of the ACMG-AMP guidelines for interpreting sequence variants and identification of areas for connected improvement.

  Niehaus A, Azzariti DR, Harrison SM, DiStefano MT, Hemphill SE, Senol-Cosar O, Rehm HL. Niehaus A, et al. Genet Med. 2019 Aug;21(viii):1699-1701. doi: 10.1038/s41436-018-0432-seven. Epub 2019 Jan 23. Genet Med. 2019. PMID: 30670879 Free PMC article. No abstract bachelor.

• Comment on the criteria for interpretation of mitochondrial tRNA variants.

  Bai R, Balog A, Kiesler P, Arjona D, Cui H. Bai R, et al. Genet Med. 2020 Aug;22(viii):1418-1419. doi: x.1038/s41436-020-0804-7. Epub 2020 May xviii. Genet Med. 2020. PMID: 32418987 No abstract available.

• Correspondence on "The role of clinical response to treatment in determining pathogenicity of genomic variants" by Shen et al.

  Biesecker LG, Harrison SM, Rehm HL. Biesecker LG, et al. Genet Med. 2021 Mar;23(three):586. doi: x.1038/s41436-020-01032-6. Epub 2020 November 6. Genet Med. 2021. PMID: 33154565 No abstruse available.

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Source: https://pubmed.ncbi.nlm.nih.gov/25741868/

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