InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines.
In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published updated standards and guidelines for the clinical interpretation of sequence variants with respect to human diseases on the basis of 28 criteria. However, variability between individual interpreters can be extensive because of reasons such as the different understandings of these guidelines and the lack of standard algorithms for implementing them, yet computational tools for semi-automated variant interpretation are not available. To address these problems, we propose a suite of methods for implementing these criteria and have developed a tool called InterVar to help human reviewers interpret the clinical significance of variants. InterVar can take a pre-annotated or VCF file as input and generate automated interpretation on 18 criteria. Furthermore, we have developed a companion web server, wInterVar, to enable user-friendly variant interpretation with an automated interpretation step and a manual adjustment step. These tools are especially useful for addressing severe congenital or very early-onset developmental disorders with high penetrance. Using results from a few published sequencing studies, we demonstrate the utility of InterVar in significantly reducing the time to interpret the clinical significance of sequence variants.
InterVar mainly consists of two major steps: (1) automated scoring on each of the 18 pieces of criteria and (2) manual review and adjustment on specific criteria to arrive at a final interpretation. During the first step, InterVar calls an annotation software, such as ANNOVAR,5 to obtain necessary annotation information on variants and then uses its own internal annotation database to supplement additional annotations. Using these annotations on variants and genes, InterVar performs a preliminary interpretation of the variant and presents all relevant evidence for manual review. Currently, 18 pieces of criteria can be automatically generated and used in the first step. During the second step, the user can manually adjust each of the criteria on the basis of prior information (such as a variant’s de novo status) or his or her own domain knowledge to reach a final interpretation. We emphasize here that automated scoring is based on default parameters and that users are advised to examine detailed evidence and use prior knowledge on ethnicity and/or disease to perform manual adjustments.
A detailed explanation of these 28 criteria is given in the Figure below.
Quan Li and Kai Wang. InterVar: Clinical interpretation of genetic variants by ACMG-AMP 2015 guideline. American Journal of Human Genetics, 100(2):267-280, 2017