title: Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.
abstract: Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Amendola
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: pair@u.washington.edu.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Center for Health Research, Kaiser Permanente, Portland, OR 97227, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Leo
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 02139, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: McLaughlin
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Yassmine
authors.initials: Y
authors.lastname: Akkari
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Amaral
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berg
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Sawona
authors.initials: S
authors.lastname: Biswas
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Bowling
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Conlin
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Cooper
authors.affiliation: Center for Precision Diagnostics, Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Dorschner
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Dulik
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Arezou A
authors.initials: AA
authors.lastname: Ghazani
authors.affiliation: Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 02139, USA; Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ragan
authors.initials: R
authors.lastname: Hart
authors.affiliation: Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Horton
authors.affiliation: Intramural Research Program, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 02139, USA; Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02115, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lebo
authors.affiliation: Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Milosavljevic
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ou
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Pak
authors.affiliation: Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ronak Y
authors.initials: RY
authors.lastname: Patel
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Punj
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Carolyn Sue
authors.initials: CS
authors.lastname: Richards
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Salama
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Natasha T
authors.initials: NT
authors.lastname: Strande
authors.affiliation: Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: Intramural Research Program, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 02139, USA; Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: hrehm@partners.org.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
mesh_terms: D035843:Biomedical Research; D003627:Data Interpretation, Statistical; D055317:Evidence-Based Practice; D059472:Exome / Q000235:genetics; D005820:Genetic Testing / Q000592:standards*; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D017408:Guidelines as Topic; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D033162:Incidental Findings; D007753:Laboratories / Q000592:standards*; D009154:Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000592:standards*; D012984:Software; D014481:United States