A large-scale resource of standardized pediatric somatic cancer variant classifications

Background: Our ability to interpret pediatric cancer genomes to identify targeted therapeutic strategies is bottlenecked by limited structured knowledge about the clinical significance of detected somatic mutations. Clinical genomics laboratories routinely keep internal records of previously classified variants in ad hoc storage systems (e.g., spreadsheets, custom databases), but significant technical barriers exist that prevent the broad dissemination of such knowledge for use across institutions. Recently developed genomic knowledge standards from the Global Alliance for Genomics and Health (GA4GH) provide the foundation to remove these barriers through a shared community framework for disseminating genomic knowledge. Methods and Results: We implemented these GA4GH standards to produce over 1,500 publicly available somatic variant classification records. These were curated as part of routine pediatric cancer genome assessment in a research hospital setting, 94% (1415/1504) of which were assessed under the Molecular Characterization Initiative of the National Cancer Institute's Childhood Cancer Data Initiative. To broadly disseminate these data, we extended the open-source “ClinVar This!” community software to ingest GA4GH-standardized records for submission to the NIH ClinVar knowledgebase. As a result, we have more than doubled the total number of somatic cancer records submitted to ClinVar (previously 1,325 records across all other community submissions). We anticipate submitting an additional 2,000 records by April 2026. To support this effort, we developed the Variation Categorizer (VarCat) web platform to simplify the structured application of community standards for clinical variant classification in a pediatric setting. The software currently supports community somatic variant classification guidelines for clinical significance (the “AMP/ASCO/CAP guidelines”) and oncogenicity (the “ClinGen/CGC/VICC guidelines”). VarCat is an open-source, clinically validated web tool that provides a streamlined mechanism for automating GA4GH-compliant dissemination of pediatric somatic cancer knowledge as part of routine clinical workflows. Conclusions: This work demonstrates how these novel GA4GH standards enable us to disseminate somatic cancer variant knowledge as part of routine clinical operations. Our presentation will highlight the use of the VarCat platform and the associated standardized variant classification data we have made publicly available. We will also share insights from our applications of these standards to capture nuanced adaptation of community guidelines for clinical variant interpretation. We will conclude with practical guidance about how to best leverage these resources as a scalable approach to addressing the variant interpretation bottleneck in the clinical setting.