56. Variants of established clinical significance: Progress and challenges in the VECS SC-VCEP

Abstract

The ClinGen Somatic Clinical Domain Working Group is working to develop and implement standards and guidelines for the curation of clinically significant cancer variants for new and emerging actionable genes. Characterizing variants with established clinical significance, especially predictive biomarkers and genomic variants with FDA-approved companion diagnostics classified under the AMP/ASCO/CAP Tier 1A category is of particular interest. However, interpreting such variants can present challenges due to insufficient detail in both the literature and FDA documentation, inadequate characterization of their function, direct correlation with disease, and associated therapeutic response. To address these challenges, the Variant of Established Clinical Significance (VECS) SC-VCEP was established to curate and maintain a comprehensive database of clinically significant somatic variants.

The VECS SC-VCEP will address a set of 15 genes: BRAF, EGFR, ERBB2, ESR1, EZH2, FGFR3, FLT3, IDH1, IDH2, KIT, KRAS, MET, NRAS, PIK3CA, and RET. Alterations in these genes are known drivers in various types of cancer and consist of SNVs, small indels, and exon loss. The VECS is piloting the ClinGen/VICC/CGC oncogenicity SOP and AMP/ASCO/CAP guidelines, focusing on 17 variants from 9 genes. The set of variants includes both well-studied and poorly characterized variants, variants that confer both resistance and sensitivity to FDA-approved drugs, and includes one representative gene from known pathways.

The VECS will determine the applicability of existing SOP codes and identify instances where additional criteria might be necessary for accurate code assignment. This initiative will ultimately provide publicly-available and high-quality oncogenic and predictive assertions to be utilized by clinicians and researchers.