26. Classifying the oncogenicity of 100 variants from pediatric cancer patients using a standardized assessment framework

Abstract

The ClinGen/CGC/VICC Oncogenicity guidelines were published in 2022 as a standardized approach for assessing a variant's capacity to promote cancer formation. We describe an assessment tool, the Variation Categorizer (VarCat), that creates highly-structured oncogenicity classifications following these guidelines suitable for a clinical laboratory setting through an intuitive user-facing web application. The resulting classification is stored in a standardized genomic knowledge format developed by the Global Alliance for Genomics and Health (GA4GH) to promote interoperability and data sharing.

Here we report our assessment of 100 somatic variants from pediatric cancer cases studied by NGS-based exome sequencing in comparison to prior assessments characterized under the AMP/ASCO/CAP clinical actionability guidelines. Our study assesses application of these complementary guidelines in a high-throughput clinical setting. We describe the frequency and impact of specific oncogenicity codes used in these variant classification assessments. Our findings highlight specific codes that would benefit from further clarification for application to clinical classification workflows pursuant to clinical testing. Of particular note, we discuss applications of the OP2 (single genetic etiology) code and the need for objective criteria that classify cited studies as providing well-established, reproducible, and robust evidence. We present the challenges created due to these subjective guidelines and present our internal framework for systematically applying these codes. We conclude with an overview of the impact of our revised assessment criteria on interpretation turn-around time and reproducibility.