52. A ClinGen Somatic curation effort focused on EGFR variants

Abstract

As next generation sequencing becomes a routine part of clinical diagnostic and follow up workup for tumor assessment, consensus on cancer variant interpretation and expanded knowledgebase curation is needed. EGFR (Epidermal Growth Factor Receptor) is a well recognized oncogene and EGFR SNVs, CNVs, indels, and fusions have important predictive, diagnostic, and prognostic roles in a variety of cancer types. A definitive collection of tumor-specific EGFR somatic variants and their responses to FDA-approved EGFR inhibitors has not yet been assembled and EGFR-specific guidelines for defining variant oncogenicity have not been proposed. Due to their growing clinical relevance, the ClinGen Somatic Clinical Domain Working Group Solid Tumor Taskforce (STTf) performed a pilot curation effort on 15 EGFR fusions, and a number of curation challenges were noted. For instance, EGFR fusions can be primary events in cancer or part of complex molecular alterations (e.g., involving amplification). The group will compile a list of EGFR fusions and collect data on characteristics such as genomic breakpoints, tumor-type associations, functional evidence, and sensitivity to inhibitors. We are forming an EGFR Somatic Cancer Variant Curation Expert Panel (EGFR SC-VCEP) to develop oncogenicity classification recommendations specific to EGFR fusions with future expansion to other EGFR sequence changes. The Step 1 ClinGen SC-VCEP application is in-progress for this effort. The results of this expert-led curation and the resulting guidelines will be publicly available through multiple avenues including the CIViC knowledgebase and ClinVar.