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

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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. Lebo, Aleksandar 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 The American Journal of Human Genetics Volume 98, Issue 6, Pages 1067-1076 (June 2016) DOI: 10.1016/j.ajhg.2016.03.024 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Distribution of Variant-Classification Comparisons according to the Extent of Differences across a Five-Tiered Classification Scheme (A) Intra-laboratory concordance between laboratory and ACMG-AMP classification systems. This graph compares each site’s use of the ACMG-AMP rules to their own laboratory classification methods. (B) Inter-laboratory concordance of 97 variants. This graph compares the same calls, based on either the ACMG-AMP rules or the site’s rules, between laboratories. (C) Inter-laboratory concordance after consensus efforts. This graph shows a final comparison of calls between sites after consensus-building efforts. The American Journal of Human Genetics 2016 98, 1067-1076DOI: (10.1016/j.ajhg.2016.03.024) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Distribution of 99 Variants Submitted for Assessment Gray outlines illustrate the distribution of variant classifications submitted for assessment. Green bars indicate those calls that were agreed upon after initial review, blue bars indicate those calls agreed upon after email exchange, and black bars indicate those calls agreed upon after discussion on conference calls. The American Journal of Human Genetics 2016 98, 1067-1076DOI: (10.1016/j.ajhg.2016.03.024) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 Frequency of Use for Each ACMG Line of Evidence The American Journal of Human Genetics 2016 98, 1067-1076DOI: (10.1016/j.ajhg.2016.03.024) Copyright © 2016 American Society of Human Genetics Terms and Conditions