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.

Figure 1

Association for Molecular Pathology (AMP) Interpretation of Sequence Variants in Somatic Conditions Working Group technical and reporting survey 1 results. A: Minor allele frequency (MAF). B: Five categories includes pathogenic, likely pathogenic, variant of unknown significance (VUS), likely benign, and benign; three categories includes pathogenic, VUS, and likely benign; other represents participant answers, such as two categories of pathogenic and VUS and no categories. List variants in order of importance for clinical impact, clinical trials, and actionability or predictive of prognosis in that tumor type or in cancer. C: Reported includes therapies approved by Food and Drug Administration (FDA) or contained in professional guidelines, or investigational therapies such as clinical trials for investigational drugs or off-label use of FDA approved drugs. D: Reported includes recommendation of genetic counseling and/or discussion with clinical team providing care to the patient. E: Variant allele frequency (VAF): the proportion (usually shown as %) of variant reads. F: Genomic coordinates of variants: genomic locations of variants denoted by the chromosome number followed by the nucleotide location of the variant (eg, chr17:7674250). G: Transcript accession information includes transcript accession number and version number (eg, NM_000546.5). H: Sometimes includes only if quality control (QC) fails for actionable/targeted variant regions. Survey results obtained anonymously from participating AMP membership regarding reporting of clinical next-generation sequencing results. AMP members are individuals involved in the clinical practice, educational, basic or translational research, economic, and/or regulatory aspects of molecular diagnostics, including but not limited to pathologists, laboratory directors, clinical laboratory scientists, informaticians, technologists, clinicians and other health care personnel, government employees, especially those involved in regulation of the field, and professionals in the in vitro diagnostics industry. Surveys were distributed through AMP's electronic member community [Chat AMP (CHAMP)], and responses were collected between April 7, 2015, and May 1, 2015. There were 44 individual responses for the reporting survey and 67 individual responses for the technical survey. For both surveys, respondents were permitted to select multiple demographic categories describing their occupation. For the technical survey, respondents self-identified as pathologist (39%), laboratory medical director (37%), researcher (15%), bioinformatician (10%), physician (8%), laboratory supervisor (12%), oncologist (3%), and clinical laboratory technologist/technician (3%). For the reporting survey, respondents self-identified as pathologist (50%), laboratory medical director (40%), researcher (13%), bioinformatician (11%), physician (8%), laboratory supervisor (8%), oncologist (3%), and clinical laboratory technologist/technician (3%).

Figure 2

Evidence-based variant categorization. Somatic variants are classified into four tiers based on their level of clinical significance in cancer diagnosis, prognosis, and/or therapeutics. Variants in tier I are of strongest clinical significance, and variants in tier IV are benign or likely benign variants. FDA, Food and Drug Administration.