ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants

Abstract

Background: The success of the clinical use of sequencing based tests (from single gene to genomes) depends on the accuracy and consistency of variant interpretation. Aiming to improve the interpretation process through practice guidelines, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have published standards and guidelines for the interpretation of sequence variants. However, manual application of the guidelines is tedious and prone to human error. Web-based tools and software systems may not only address this problem but also document reasoning and supporting evidence, thus enabling transparency of evidence-based reasoning and resolution of discordant interpretations.

Results: In this report, we describe the design, implementation, and initial testing of the Clinical Genome Resource (ClinGen) Pathogenicity Calculator, a configurable system and web service for the assessment of pathogenicity of Mendelian germline sequence variants. The system allows users to enter the applicable ACMG/AMP-style evidence tags for a specific allele with links to supporting data for each tag and generate guideline-based pathogenicity assessment for the allele. Through automation and comprehensive documentation of evidence codes, the system facilitates more accurate application of the ACMG/AMP guidelines, improves standardization in variant classification, and facilitates collaborative resolution of discordances. The rules of reasoning are configurable with gene-specific or disease-specific guideline variations (e.g. cardiomyopathy-specific frequency thresholds and functional assays). The software is modular, equipped with robust application program interfaces (APIs), and available under a free open source license and as a cloud-hosted web service, thus facilitating both stand-alone use and integration with existing variant curation and interpretation systems. The Pathogenicity Calculator is accessible at http://calculator.clinicalgenome.org .

Conclusions: By enabling evidence-based reasoning about the pathogenicity of genetic variants and by documenting supporting evidence, the Calculator contributes toward the creation of a knowledge commons and more accurate interpretation of sequence variants in research and clinical care.

Keywords: ACMG guidelines; Big Data; ClinGen; ClinVar; Clinical Genome Resource; Clinical exome sequencing; Clinical genome sequencing; Data commons; Data sharing; Exome sequencing; Genome sequencing; Knowledge commons; Linked Data.

Fig. 1

Four-panel interface for the ClinGen Pathogenicity Calculator

Fig. 2

a Interface for initializing an evidence document for a selected allele by adding information about disease condition and mode of inheritance. b Interface for updating tags by clicking on a cell and selecting a tag from a pull-down menu. A link to a table defining tags in each cell (such as a table with ACMG tags) is provided for reference. c Interface for updating links to supporting data for a tag by opening the “Manage Links” tab in panel B and by entering one or more URLs/Links along with any free-text comments. d An alternate interface to manage tags and provide summary and links. This interface lists all the tags for each evidence type (e.g. Population Data, Computational Data, etc.). This panel is activated by clicking on the evidence type in the left-most column of the evidence summary table (Fig. 1, left-most column in the bottom panel)

Fig. 3

A sample summary report generated by Pathogenicity Calculator. The report itself is printable as PDF and downloadable by the user