title: ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants.
abstract: 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.
  
  
  
  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 .
  
  
  
  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.
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA. ronak.patel@bcm.edu.
authors.forename: Ronak Y
authors.initials: RY
authors.lastname: Patel
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Neethu
authors.initials: N
authors.lastname: Shah
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Jackson
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Pawliczek
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Paithankar
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Baker
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Riehle
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Hailin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Milosavljevic
authors.affiliation: The Renaissance Computing Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27517, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Bizon
authors.affiliation: University of Utah Hospitals and Clinics, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Rynearson
authors.affiliation: Geisinger autism and developmental medicine, Lewisburg, PA, 17837, USA.
authors.forename: Tristan
authors.initials: T
authors.lastname: Nelson
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, 02139, USA.|Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, 02139, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Harrison
authors.affiliation: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, 02139, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Azzariti
authors.affiliation: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
authors.forename: Bradford
authors.initials: B
authors.lastname: Powell
authors.affiliation: GeneInsight, Sunquest Information System, Boston, MA, 02210, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Babb
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: Baylor College of Medicine, Houston, TX, 77030, USA. amilosav@bcm.edu.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Milosavljevic
mesh_terms: D000483:Alleles; D019295:Computational Biology; D004194:Disease / Q000235:genetics*; D014644:Genetic Variation; D005826:Genetics, Medical; D015894:Genome, Human; D017408:Guidelines as Topic; D006801:Humans; D009154:Mutation; D012984:Software
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