Sequence Variant Interpretation 2.0: Perspective on New Guidelines for Sequence Variant Classification.

Abstract

Diagnostic tests based on next-generation sequencing (NGS),5 including gene-panel, exome, and whole-genome sequencing, are routinely performed worldwide. Although the technical validity of NGS-based tests continues to improve rapidly, the community is working to demonstrate the clinical validity and utility of these methods, which largely depend on our ability to interpret all sequence variants in a thorough, reproducible, timely, and clinically relevant manner. Accurately interpreting variants is challenging. The large volume of variants; the lack of curated information regarding the relationship between variants, gene functions, and clinical consequences; and the lack of consistent roles that capture all aspects of a variant's impact on the normal functions of a gene product are some of the challenges faced by medical geneticists, genetic counselors, and molecular pathologists specializing in molecular diagnostic services. The American College of Medical Genetics and Genomics (ACMG), the Association for Molecular Pathology, and the College of American Pathologists recently jointly released standards and guidelines for the interpretation of sequence variants (1). This collective effort by society leadership groups and the whole genetics community aims to address the above challenges and represents a milestone in NGS-based diagnostic testing. The first set of ACMG variant interpretation guidelines was released in 2008, at a time when Sanger sequencing was the main method of single gene variant detection and molecular diagnostic testing (2). In the 2008 version of these guidelines (referred to here as guidelines 1.0), the decision tree for interpreting a sequence variant started with whether a variant was previously reported as causative of the disease and followed with a prediction based on the nature or type of a variant. Because NGS-based tests often detect numerous previously unreported variants, a classification system based on previously reported variants is of very limited use. Furthermore, population-based exome and whole-genome sequencing projects suggest that many …