InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines - PubMed (original) (raw)

InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines

Quan Li et al. Am J Hum Genet. 2017.

Abstract

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.

Keywords: ACMG; ANNOVAR; ClinVar; InterVar; clinical interpretation; genetic diagnosis; variant annotation; variant interpretation.

Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1

Flowchart of the Two-Step Procedure of InterVar Underlined and bold fonts denote automated criteria.

Figure 2

Figure 2

Illustration of the 28 Criteria from the 2015 ACMG-AMP Guidelines For some criteria, the name of the internal database and its size are denoted within parentheses.

Figure 3

Figure 3

AAF Distribution of Pathogenic or Likely Pathogenic ClinVar Variants Predicted to Be Benign or Likely Benign by InterVar and All Pathogenic or Likely Pathogenic ClinVar Variants

Figure 4

Figure 4

Illustration of wInterVar (A) Automatic interpretation of genetic variants, which can be entered by several means. (B) Once users click “adjust,” the full list of criteria is shown for manual adjustment, after which the final results are given.

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