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

Patel RY1, Shah N2, Jackson AR2, Ghosh R2, Pawliczek P2, Paithankar S2, Baker A2, Riehle K2, Chen H2, Milosavljevic S2, Bizon C3, Rynearson S4, Nelson T5, Jarvik GP6, Rehm HL7,8, Harrison SM7, Azzariti D7, Powell B9, Babb L10, Plon SE2, Milosavljevic A11; ClinGen Resource.

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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