Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes, and epigenetic assays for genetic disorders. By virtue of increased complexity, this shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context the ACMG convened a workgroup in 2013 comprising representatives from the ACMG, the Association for Molecular Pathology (AMP), and the College of American Pathologists to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP, and College of American Pathologists stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. This report recommends the use of specific standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified in genes that cause Mendelian disorders. Moreover, this recommendation describes a process for classifying variants into these five categories based on criteria using typical types of variant evidence (e.g., population data, computational data, functional data, segregation data). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments-approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
Department of Molecular and Medical Genetics, Knight Diagnostic Laboratories, Oregon Health & Science University, Portland, Oregon, USA.
Sue
S
Richards
1] College of American Pathologists, Chicago, Illinois, USA [2] Current affiliation: Phoenix Children's Hospital, Phoenix, Arizona, USA.
Nazneen
N
Aziz
GeneDx, Gaithersburg, Maryland, USA.
Sherri
S
Bale
Department of Pediatrics, Section of Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
David
D
Bick
Department of Human Genetics, Clinical Molecular Genetics Laboratory, The University of Chicago, Chicago, Illinois, USA.
Soma
S
Das
1] Cytogenetics/Molecular Genetics Laboratory, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, USA [3] Department of Pediatrics, Ohio State University College of Medicine, Columbus, Ohio, USA.
Julie
J
Gastier-Foster
1] Department of Pathology and Laboratory Medicine, University of California Los Angeles School of Medicine, Los Angeles, California, USA [2] Department of Pediatrics, University of California Los Angeles School of Medicine, Los Angeles, California, USA [3] Department of Human Genetics, University of California Los Angeles School of Medicine, Los Angeles, California, USA.
Wayne W
WW
Grody
Department of Human Genetics, Emory Genetics Laboratory, Emory University, Atlanta, Georgia, USA.
Madhuri
M
Hegde
Department of Pathology, ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, Utah, USA.
Elaine
E
Lyon
Department of Pediatrics, Molecular Genetics Laboratory, Children's Hospital Colorado, University of Colorado Anschutz Medical School, Denver, Colorado, USA.
Elaine
E
Spector
Department of Pathology, ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, Utah, USA.
Karl
K
Voelkerding
Partners Laboratory for Molecular Medicine and Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Heidi L
0000000260250015
HL
Rehm
D016022:Case-Control Studies; D005787:Gene Frequency; D005820:Genetic Testing / Q000592:standards*; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D016017:Odds Ratio; D017422:Sequence Analysis, DNA / Q000592:standards*