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

Abstract

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.

Conflict of interest statement

Conflicts of Interest: All workgroup members are clinical service providers. No commercial conflict of interest was reported for Sue Richards, David Bick, Soma Das, Wayne Grody, Elaine Spector, Julie Gastier-Foster, Nazneen Aziz, and Karl Voelkerding. The following workgroup members have a commercial conflict of interest: Sherri Bale (GeneDx, BioReference (stock), Advisory boards for RainDance, Ingenuity); Madhuri Hegde (Advisor for: Oxford Genetic Technologies, Tessarae, Ingenuity/Qiagen); Elaine Lyon (Advisory board for Complete Genomics); and Heidi Rehm (Scientific advisory boards: Ingenuity/Qiagen, Complete Genomics, Knome, Focused Genomics).

Figures

Figure 1. Evidence Framework

The following chart organizes each of the criteria by the type of evidence as well as the strength of the criteria for a benign (left side) or pathogenic (right side) assertion. Evidence code descriptions can be found in Tables 3 and 4. Abbreviations: BS, benign strong; BP, benign supporting; FH, family history; LOF, loss-of-function; MAF, minor allele frequency; path., pathogenic; PM, pathogenic moderate; PP, pathogenic supporting; PS, pathogenic strong; PVS, pathogenic very strong