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

Laura M. Amendola, Kathleen Muenzen, Leslie G. Biesecker, Kevin M. Bowling, Greg M. Cooper, Michael O. Dorschner, Catherine Driscoll, Ann Katherine M. Foreman, Katie Golden-Grant, John M. Greally, Lucia Hindorff, Dona Kanavy, Vaidehi Jobanputra, Jennifer J. Johnston, Eimear E. Kenny, Shannon McNulty, Priyanka Murali, Jeffrey Ou, Bradford C. Powell, Heidi L. RehmBradley Rolf, Tamara S. Roman, Jessica Van Ziffle, Saurav Guha, Avinash Abhyankar, David Crosslin, Eric Venner, Bo Yuan, Hana Zouk, Gail P. Jarvik

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)932-941
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - Nov 5 2020


  • ACMG-AMP recommendations
  • genomic implementation
  • germline variant classification

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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