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Am J Hum Genet. 2016 Jun 2;98(6):1067-1076. doi: 10.1016/j.ajhg.2016.03.024. Epub 2016 May 12.

Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.

Author information

1
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
2
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: pair@u.washington.edu.
3
Center for Health Research, Kaiser Permanente, Portland, OR 97227, USA.
4
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 02139, USA.
5
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
6
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
7
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
8
Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
9
Center for Precision Diagnostics, Department of Pathology, University of Washington, Seattle, WA 98195, USA.
10
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
12
Baylor College of Medicine, Houston, TX 77030, USA.
13
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.
14
Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
15
Intramural Research Program, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
16
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.
17
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.

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.

PMID:
27181684
PMCID:
PMC4908185
DOI:
10.1016/j.ajhg.2016.03.024
[Indexed for MEDLINE]
Free PMC Article

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