title: Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.
abstract: Widespread clinical laboratory implementation of next-generation sequencing-based cancer testing has highlighted the importance and potential benefits of standardizing the interpretation and reporting of molecular results among laboratories. A multidisciplinary working group tasked to assess the current status of next-generation sequencing-based cancer testing and establish standardized consensus classification, annotation, interpretation, and reporting conventions for somatic sequence variants was convened by the Association for Molecular Pathology with liaison representation from the American College of Medical Genetics and Genomics, American Society of Clinical Oncology, and College of American Pathologists. On the basis of the results of professional surveys, literature review, and the Working Group's subject matter expert consensus, a four-tiered system to categorize somatic sequence variations based on their clinical significances is proposed: tier I, variants with strong clinical significance; tier II, variants with potential clinical significance; tier III, variants of unknown clinical significance; and tier IV, variants deemed benign or likely benign. Cancer genomics is a rapidly evolving field; therefore, the clinical significance of any variant in therapy, diagnosis, or prognosis should be reevaluated on an ongoing basis. Reporting of genomic variants should follow standard nomenclature, with testing method and limitations clearly described. Clinical recommendations should be concise and correlate with histological and clinical findings.
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, the Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address: lim5@email.chop.edu.
authors.forename: Marilyn M
authors.initials: MM
authors.lastname: Li
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Duke University School of Medicine, Durham, North Carolina.
authors.forename: Michael
authors.initials: M
authors.lastname: Datto
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Duncavage
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Baylor Genetics, Houston, Texas.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Neal I
authors.initials: NI
authors.lastname: Lindeman
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Somak
authors.initials: S
authors.lastname: Roy
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Vnencak-Jones
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Daynna J
authors.initials: DJ
authors.lastname: Wolff
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.affiliation: Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
mesh_terms: D004252:DNA Mutational Analysis / Q000592:standards*; D030541:Databases, Genetic; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing / Q000592:standards*; D006801:Humans; D025202:Molecular Diagnostic Techniques; D058977:Molecular Sequence Annotation; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics*; D012015:Reference Standards