title: A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.
abstract: Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research.
  
  
  
  We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability.
  
  
  
  We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders.
  
  
  
  The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258-1268.
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA.
authors.forename: Jessica Ezzell
authors.identifier: 0000-0002-1117-1097
authors.initials: JE
authors.lastname: Hunter
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Irving
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.affiliation: Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA.
authors.forename: Adam
authors.identifier: 0000-0002-6518-2453
authors.initials: A
authors.lastname: Buchanan
authors.affiliation: Division of Cardiology, University of North Carolina School of Medicine, McAllister Heart Institute, Chapel Hill, North Carolina, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Jensen
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Kristy
authors.identifier: 0000-0002-8338-7989
authors.initials: K
authors.lastname: Lee
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA.
authors.forename: Christa Lese
authors.initials: CL
authors.lastname: Martin
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Milko
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA.
authors.forename: Kristin
authors.identifier: 0000-0001-9883-2224
authors.initials: K
authors.lastname: Muessig
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Annie D
authors.identifier: 0000-0001-9425-3073
authors.initials: AD
authors.lastname: Niehaus
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Julianne
authors.identifier: 0000-0001-5843-4432
authors.initials: J
authors.lastname: O'Daniel
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA.
authors.forename: Margaret A
authors.identifier: 0000-0002-6231-9653
authors.initials: MA
authors.lastname: Piper
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Ramos
authors.affiliation: Office of Disease Prevention, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sheri D
authors.identifier: 0000-0003-1550-9224
authors.initials: SD
authors.lastname: Schully
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nara
authors.initials: N
authors.lastname: Sobreira
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Strande
authors.affiliation: American College of Medical Genetics and Genomics, Bethesda, Maryland, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Weaver
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA.
authors.forename: Elizabeth M
authors.identifier: 0000-0002-0128-133X
authors.initials: EM
authors.lastname: Webber
authors.affiliation: Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA.
authors.forename: Marc S
authors.identifier: 0000-0001-6165-8701
authors.initials: MS
authors.lastname: Williams
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Jonathan S
authors.identifier: 0000-0003-2360-2664
authors.initials: JS
authors.lastname: Berg
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: James P
authors.identifier: 0000-0002-4080-8077
authors.initials: JP
authors.lastname: Evans
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA.
authors.forename: Katrina A B
authors.identifier: 0000-0001-9535-8993
authors.initials: KA
authors.lastname: Goddard
mesh_terms: D059472:Exome / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000473:pathology; D005820:Genetic Testing; D014644:Genetic Variation; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D057285:Precision Medicine