Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium

Laura M. Amendola, Gail P. Jarvik, Michael C. Leo, Heather M. McLaughlin, Yassmine Akkari, Michelle D. Amaral, Jonathan S. Berg, Sawona Biswas, Kevin M. Bowling, Laura K. Conlin, Greg M. Cooper, Michael O. Dorschner, Matthew C. Dulik, Arezou A. Ghazani, Rajarshi Ghosh, Robert C. Green, Ragan Hart, Carrie Horton, Jennifer J. Johnston, Matthew S. LeboAleksandar Milosavljevic, Jeffrey Ou, Christine M. Pak, Ronak Y. Patel, Sumit Punj, Carolyn Sue Richards, Joseph Salama, Natasha T. Strande, Yaping Yang, Sharon E. Plon, Leslie G. Biesecker, Heidi L. Rehm

Research output: Contribution to journalArticlepeer-review

339 Scopus citations


Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.

Original languageEnglish (US)
Pages (from-to)1067-1076
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - Jun 2 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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