title: Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar.
abstract: Data sharing through ClinVar offers a unique opportunity to identify interpretation differences between laboratories. As part of a ClinGen initiative, four clinical laboratories (Ambry, GeneDx, Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory) collaborated to identify the basis of interpretation differences and to investigate if data sharing and reassessment resolve interpretation differences by analyzing a subset of variants.
  
  
  
  ClinVar variants with submissions from at least two of the four participating laboratories were compared. For a subset of identified differences, laboratories documented the basis for discordance, shared internal data, independently reassessed with the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines, and then compared interpretations.
  
  
  
  At least two of the participating laboratories interpreted 6,169 variants in ClinVar, of which 88.3% were initially concordant. Laboratories reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing; 12.8% (31) of reassessed variants remained discordant owing to differences in the application of the ACMG-AMP guidelines.
  
  
  
  Participating laboratories increased their overall concordance from 88.3 to 91.7%, indicating that sharing variant interpretations in ClinVar-thereby allowing identification of differences and motivation to resolve those differences-is critical to moving toward more consistent variant interpretations.Genet Med advance online publication 09 March 2017.
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Steven M
authors.identifier: 0000-0002-9614-9111
authors.initials: SM
authors.lastname: Harrison
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Jill S
authors.identifier: 0000-0002-3854-9539
authors.initials: JS
authors.lastname: Dolinsky
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Knight Johnson
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Pesaran
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts, USA.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Azzariti
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.|Department of Pediatrics, Division of Genetics and Genomics, University of California Irvine, Irvine, California, USA.
authors.forename: Elizabeth C
authors.identifier: 0000-0002-4082-371X
authors.initials: EC
authors.lastname: Chao
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Vincent
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham &Women's Hospital, Boston, Massachusetts, USA.|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Heidi L
authors.identifier: 0000-0002-6025-0015
authors.initials: HL
authors.lastname: Rehm
mesh_terms: D002984:Clinical Laboratory Information Systems / Q000592:standards*; D019411:Clinical Laboratory Techniques / Q000592:standards*; D030541:Databases, Genetic; D005820:Genetic Testing / Q000592:standards; D014644:Genetic Variation / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D033181:Information Dissemination / Q000379:methods; D007753:Laboratories / Q000592:standards; D012984:Software