%0 Journal Article %J Am J Hum Genet %D 2020 %T Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies. %A Amendola, Laura M %A Muenzen, Kathleen %A Biesecker, Leslie G %A Bowling, Kevin M %A Cooper, Greg M %A Dorschner, Michael O %A Driscoll, Catherine %A Foreman, Ann Katherine M %A Golden-Grant, Katie %A Greally, John M %A Hindorff, Lucia %A Kanavy, Dona %A Jobanputra, Vaidehi %A Johnston, Jennifer J %A Kenny, Eimear E %A McNulty, Shannon %A Murali, Priyanka %A Ou, Jeffrey %A Powell, Bradford C %A Rehm, Heidi L %A Rolf, Bradley %A Roman, Tamara S %A Van Ziffle, Jessica %A Guha, Saurav %A Abhyankar, Avinash %A Crosslin, David %A Eric Venner %A Bo Yuan %A Zouk, Hana %A Jarvik, Gail P %K Cardiovascular Diseases %K Computational Biology %K Genetic Testing %K Genetic Variation %K Genetics, Medical %K Genome, Human %K Genomics %K High-Throughput Nucleotide Sequencing %K Humans %K Laboratories %K Laboratory Proficiency Testing %K Neoplasms %K Sequence Analysis, DNA %K Software %K Terminology as Topic %X

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.

%B Am J Hum Genet %V 107 %P 932-941 %8 2020 Nov 05 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/33108757?dopt=Abstract %R 10.1016/j.ajhg.2020.09.011 %0 Journal Article %J Am J Hum Genet %D 2016 %T Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine. %A Green, Robert C %A Goddard, Katrina A B %A Jarvik, Gail P %A Amendola, Laura M %A Appelbaum, Paul S %A Berg, Jonathan S %A Bernhardt, Barbara A %A Biesecker, Leslie G %A Biswas, Sawona %A Blout, Carrie L %A Bowling, Kevin M %A Brothers, Kyle B %A Burke, Wylie %A Caga-Anan, Charlisse F %A Chinnaiyan, Arul M %A Chung, Wendy K %A Clayton, Ellen W %A Cooper, Gregory M %A East, Kelly %A Evans, James P %A Fullerton, Stephanie M %A Garraway, Levi A %A Garrett, Jeremy R %A Gray, Stacy W %A Henderson, Gail E %A Hindorff, Lucia A %A Holm, Ingrid A %A Lewis, Michelle Huckaby %A Hutter, Carolyn M %A Janne, Pasi A %A Joffe, Steven %A Kaufman, David %A Knoppers, Bartha M %A Koenig, Barbara A %A Krantz, Ian D %A Manolio, Teri A %A McCullough, Laurence %A McEwen, Jean %A McGuire, Amy %A Muzny, Donna %A Myers, Richard M %A Nickerson, Deborah A %A Ou, Jeffrey %A Parsons, Donald W %A Petersen, Gloria M %A Plon, Sharon E %A Rehm, Heidi L %A Roberts, J Scott %A Robinson, Dan %A Salama, Joseph S %A Scollon, Sarah %A Sharp, Richard R %A Shirts, Brian %A Spinner, Nancy B %A Tabor, Holly K %A Tarczy-Hornoch, Peter %A Veenstra, David L %A Wagle, Nikhil %A Weck, Karen %A Wilfond, Benjamin S %A Wilhelmsen, Kirk %A Wolf, Susan M %A Wynn, Julia %A Yu, Joon-Ho %K Adult %K Biomedical Research %K Cardiovascular Diseases %K Child %K Clinical Trials as Topic %K Evidence-Based Practice %K Exome %K Genome, Human %K Genomics %K High-Throughput Nucleotide Sequencing %K Humans %K National Human Genome Research Institute (U.S.) %K Polymorphism, Single Nucleotide %K Population Groups %K Software %K United States %X

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

%B Am J Hum Genet %V 98 %P 1051-1066 %8 2016 Jun 02 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/27181682?dopt=Abstract %R 10.1016/j.ajhg.2016.04.011