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

Marilyn M Li; Michael Datto; Eric J Duncavage; Shashikant Kulkarni; Neal I Lindeman; Somak Roy; Apostolia M Tsimberidou; Cindy L Vnencak-Jones; Daynna J Wolff; Anas Younes; Marina N Nikiforova

doi:10.1016/j.jmoldx.2016.10.002

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

J Mol Diagn. 2017 Jan;19(1):4-23. doi: 10.1016/j.jmoldx.2016.10.002.

Authors

Affiliations

¹ 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: [email protected].
² 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.
³ 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.
⁴ Interpretation of Sequence Variants in Somatic Conditions Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Bethesda, Maryland; Baylor Genetics, Houston, Texas.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.

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.

Publication types

Guideline
Review
Research Support, Non-U.S. Gov't

MeSH terms

DNA Mutational Analysis / standards*
Databases, Genetic
Genetic Testing
High-Throughput Nucleotide Sequencing / standards*
Humans
Molecular Diagnostic Techniques
Molecular Sequence Annotation
Neoplasms / diagnosis
Neoplasms / genetics*
Reference Standards

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States