title: The challenge of comprehensive and consistent sequence variant interpretation between clinical laboratories.
abstract: OBJECTIVE
  Genetic testing has shifted from academic laboratories with expertise in specific genes to commercial laboratories that offer tests of a diverse array of genes. The purpose of this comparative study was to determine whether one academic laboratory's model of variant interpretation is similar to that of several commercial laboratories.
  
  
  METHODS
  The Collagen Diagnostic Laboratory (CDL) received, over a 14-month period, 38 requests to interpret variants originally identified by an outside laboratory (OL). The interpretations by the OL and CDL were compared and discrepancies were assessed.
  
  
  RESULTS
  Interpretations from the OL and CDL were concordant in 11 inquiries (29%); discrepancies were moderate in 11 instances (29%) and significant in 16 (42%). Factors that caused discrepancies included the following: (i) private data were not shared in a public database (n = 9); (ii) publicly available allele frequency data were not referenced and used as evidence (n = 5); and (iii) important aspects of protein structure and function were not taken into account (n = 13).
  
  
  CONCLUSIONS
  Comprehensive interpretation of sequence variants depends on good functional tests and well-curated variant databases. Provision of clinical information to the clinical laboratory, mandatory submission of identified variants with phenotype data to common resources, and collaboration between clinical laboratories and recognized experts is likely to improve consistency in variant interpretation among clinical laboratories.Genet Med 18 1, 20-24.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Melanie G
authors.identifier: http://orcid.org/0000-0001-6299-2971
authors.initials: MG
authors.lastname: Pepin
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.|Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Mitzi L
authors.initials: ML
authors.lastname: Murray
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bailey
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Dru
authors.initials: D
authors.lastname: Leistritz-Kessler
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schwarze
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.|Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Peter H
authors.identifier: http://orcid.org/0000-0001-7786-7030
authors.initials: PH
authors.lastname: Byers
mesh_terms: D003627:Data Interpretation, Statistical; D005787:Gene Frequency; D056726:Genetic Association Studies; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation; D006801:Humans; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA / Q000379:methods*
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