ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene‐level specification of the ACMG/AMP guidelines for sequence variant interpretation

Abstract

Genome-scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high-quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health (NIH), is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen Variant Curation Expert Panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures (SOPs) for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants.

Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework

“…In response to calls to further standardize variant interpretation [3,4], the Clinical Genome Resource (ClinGen) established the Sequence Variant Interpretation Working Group (SVI) [5] and condition-specific Variant Curation Expert Panels (VCEPs) to refine ACMG/AMP guidelines for each evidence criterion [6]. To date, six VCEPs have published recommendations, including their assay validation requirements and which assays were ultimately approved for PS3/BS3 evidence application [7][8][9][10][11][12].…”

“…VCEP-approved assays varied greatly and included splicing assays, animal and cellular models, and different in vitro systems [Kanavy et al, submitted]. VCEPs generally approved assays that considered the disease mechanism and most included wild-type controls, but statistical analyses and the inclusion of other controls were less 6 consistent. The VCEPs vary significantly in how they defined which assays were "wellestablished" [Kanavy et al, submitted], including consideration of parameters such as experimental design, replication, controls, and validation, indicating the subjective nature of assessing the quality and applicability of functional evidence, potentially leading to discordance in variant classification.…”

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

“…These guidelines are intended to be generic, and thus some evidence codes will not be relevant for variant curation for a specific gene. The ClinGen consortium (Rehm et al, ; https://www.clinicalgenome.org/) has engaged with expert groups to develop adaptations of the guidelines to specify which rule codes and strengths are appropriate for a specific gene‐disease relationship, and to provide guidance on the phenotypic features that are most predictive of variant pathogenicity (Rivera‐Munoz et al, ). To date, adaptations of the ACMG/AMP criteria have been completed for two hereditary cancer genes: PTEN (Mester et al, ) and CDH1 (Lee et al, ), whereas other gene‐adaptations are in development.…”

How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies

“…6,7 To encourage genomic and phenotypic data sharing, and engage experts in consensus-driven variant interpretation, the Clinical Genome Resource (ClinGen) convened Variant Curation Expert Panels (VCEP) to develop gene-and disease-specific modifications of the original guidelines and provide expert-reviewed variant classification for depositing into ClinVar (Online Supplementary Figure S1). 17 In 2018, the American Society of Hematology (ASH) sponsored a ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP), composed of 34 international members, who started working on gene-and disease-specific rules for RUNX1 as the first of several genes conferring predisposition to myeloid malignancies (Online Supplementary Figure S1A). After designing, modifying and testing the preliminary RUNX1 rules on 52 pilot variants, which improved classification in 33% VUS or variants with conflicting interpretations (CONF), MM-VCEPspecified ACMG/AMP rules were approved by the ClinGen oversight committee and efforts to curate variants to ClinVar using the Variant Curation Interface have commenced (Online Supplementary Figure S1B).…”