. 2020 Nov 5;107(5):932-941.

doi: 10.1016/j.ajhg.2020.09.011. Epub 2020 Oct 26.

Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies

Laura M Amendola¹, Kathleen Muenzen², Leslie G Biesecker³, Kevin M Bowling⁴, Greg M Cooper⁴, Michael O Dorschner⁵, Catherine Driscoll³, Ann Katherine M Foreman⁶, Katie Golden-Grant⁵, John M Greally⁷, Lucia Hindorff⁸, Dona Kanavy⁶, Vaidehi Jobanputra⁹, Jennifer J Johnston³, Eimear E Kenny¹⁰, Shannon McNulty⁶, Priyanka Murali⁵, Jeffrey Ou⁵, Bradford C Powell⁶, Heidi L Rehm¹¹, Bradley Rolf⁵, Tamara S Roman⁶, Jessica Van Ziffle¹², Saurav Guha¹³, Avinash Abhyankar¹³, David Crosslin², Eric Venner¹⁴, Bo Yuan¹⁵, Hana Zouk¹⁶; CSER Sequencing and Diagnostic Yield working group; Gail P Jarvik⁵

Affiliations

¹ Department of Medicine, Division of Medical Genetics, University of Washington Medical Center, Seattle, WA 98195, USA. Electronic address: lauraa7@uw.edu.
² Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195, USA.
³ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
⁴ Hudson Alpha Institute for Biotechnology, Huntsville, AL 35806, USA.
⁵ Department of Medicine, Division of Medical Genetics, University of Washington Medical Center, Seattle, WA 98195, USA.
⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁸ Division of Genomic Medicine, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
⁹ New York Genome Center, New York, NY 10013, USA; Columbia University Medical Center, New York, NY 10032, USA.
¹⁰ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹ Massachusetts General Hospital and the Broad Institute of MIT and Harvard, Boston, MA 02142, USA.
¹² Department of Pathology, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
¹³ New York Genome Center, New York, NY 10013, USA.
¹⁴ Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Genetics, Houston, TX 77030, USA.
¹⁶ Department of Pathology, Massachusetts General Hospital, Harvard Medical School and Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Boston, MA 02139, USA.

PMID: 33108757
PMCID: PMC7675005
DOI: 10.1016/j.ajhg.2020.09.011

Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies

Laura M Amendola et al. Am J Hum Genet. 2020.

. 2020 Nov 5;107(5):932-941.

doi: 10.1016/j.ajhg.2020.09.011. Epub 2020 Oct 26.

Authors

Affiliations

¹ Department of Medicine, Division of Medical Genetics, University of Washington Medical Center, Seattle, WA 98195, USA. Electronic address: lauraa7@uw.edu.
² Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195, USA.
³ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
⁴ Hudson Alpha Institute for Biotechnology, Huntsville, AL 35806, USA.
⁵ Department of Medicine, Division of Medical Genetics, University of Washington Medical Center, Seattle, WA 98195, USA.
⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁸ Division of Genomic Medicine, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
⁹ New York Genome Center, New York, NY 10013, USA; Columbia University Medical Center, New York, NY 10032, USA.
¹⁰ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹ Massachusetts General Hospital and the Broad Institute of MIT and Harvard, Boston, MA 02142, USA.
¹² Department of Pathology, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
¹³ New York Genome Center, New York, NY 10013, USA.
¹⁴ Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Genetics, Houston, TX 77030, USA.
¹⁶ Department of Pathology, Massachusetts General Hospital, Harvard Medical School and Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Boston, MA 02139, USA.

PMID: 33108757
PMCID: PMC7675005
DOI: 10.1016/j.ajhg.2020.09.011

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.

Keywords: ACMG-AMP recommendations; genomic implementation; germline variant classification.

PubMed Disclaimer

Conflict of interest statement

L.G.B. is an uncompensated member of the Illumina Corp medical ethics advisory board and receives in-kind research support from Arqule, Inc., now wholly owned by Merck, Inc.

Figures

**Figure 1**
Discordant Variant Discussion Process and Outcomes

**Figure 2**
Common Reasons for Variant Classification Discordance

See this image and copyright information in PMC

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Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies

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Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies

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