Abstract 6578: reVUE: repository for variants with unexpected effects

Abstract Clinical sequencing of tumor samples is now a component of routine cancer care used to identify predictive biomarkers of drug response, refine patient cancer diagnoses, assess heritable cancer risk, or inform patient prognosis. Most genomic alterations are accurately annotated with tools such as the Variant Effect Predictor (VEP) that infer the effects of these alterations on the mRNA and protein by following basic rules of transcription, mRNA post-transcriptional processing, and translation. However, some genomic variants are not as easily captured by these rules, which can cause inappropriate or unclear annotation of the protein effect. For example, a variant that alters an existing splice site or creates a new one can activate or inactivate the protein. Similarly, specific mutations in the non-coding promoter region of a gene may de-regulate gene expression (e.g., TERT promoter mutations). In some instances, these so-called variants with unexpected effects (VUE) may have therapeutic implications. For example, while ~2-3% of GIST tumors harbor KIT exon 11 deletions that extend into the non-coding intron between exons 10 and 11 and are shown to cause in-frame deletions, they are typically misclassified as inactivating splice site mutations, precluding patients with tumors harboring these mutations from receiving standard care imatinib. Thus, while many VUEs are functionally characterized and documented in the literature, there are no resources to systematically identify, curate and store these events such that they can be correctly annotated in routine clinical sequencing leading to suboptimal treatment decisions. To address this unmet clinical need, we built a novel bioinformatic resource, the Repository for Variants with Unexpected Effects (reVUE - cancerrevue.org). The reVUE resource consists of (1) an intuitive website listing curated VUEs with their observed effects as demonstrated by functional characterization in peer-reviewed literature and (2) an application programming interface (API) for programmatic annotation of variants. We built reVUE as a crowd-sourced resource to enable contributions of VUEs to the repository from the clinical and scientific communities. Both the software and data are openly available. Our goal is to enable clinical bioinformatic pipelines to accurately annotate all DNA mutations, including those with unanticipated protein coding effects, some of which can have therapeutic implications. Citation Format: Ino de Bruijn, Aditi Gopalan, Xiang Li, Hongxin Zhang, Onur Sumer, Thomas Y. Cong, Tona Gonzalez, Madelaine Rangel, Nikolaus Schultz, Debyani Chakravarty. reVUE: repository for variants with unexpected effects. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6578.