Variant interpretation web services for precision oncology: Genome Nexus and reVUE

Accurate interpretation of genomic alterations is essential for precision oncology, yet variant information remains dispersed across heterogeneous resources. To streamline access to high-quality annotations, we present recent advancements to Genome Nexus (genomenexus.org) and reVUE (cancerrevue.org), two complementary open-source web services that together provide an integrated ecosystem for interpreting both canonical and atypical cancer variants. Genome Nexus aggregates functional, structural, population, and clinical evidence from a broad collection of cancer- and genome-focused databases. Through a unified API and intuitive interface, it harmonizes variant effect predictions, protein annotations, variant population frequencies, mutational hotspot and driver information, and clinical actionability from resources such as VEP, UniProt, Pfam, gnomAD, Cancer Hotspots, CIViC, OncoKB, and ClinVar. Recent enhancements include improved selection of canonical transcripts for routine clinical cancer care, expanded handling of transcript versioning, and optimized annotation performance. Genome Nexus enables high-throughput variant annotation, supports interactive browsing, and is integrated into cBioPortal and used by AACR Project GENIE. A subset of genomic alterations exhibit variants with unexpected effects (VUEs), whose molecular consequences diverge from those predicted by standard annotation rules. These variants are frequently mis-annotated despite documented functional evidence in the literature. To address this gap, we developed reVUE, an open-source curated repository and API cataloging experimentally validated VUEs, including therapeutically relevant alterations in genes such as KIT, MET, ATM, EGFR, and BRCA1/2. The resource continues to expand, with several newly curated VUEs added across multiple cancer-associated genes. reVUE is fully integrated into Genome Nexus, ensuring that both predictable and atypical variant effects are captured within a unified interpretation workflow. Together, Genome Nexus and reVUE advance the accuracy and completeness of cancer variant interpretation by consolidating diverse evidence sources, incorporating expert-curated annotations for complex variant classes, and providing scalable programmatic access. As open-source resources, they support transparent, reproducible, and extensible workflows that enhance precision oncology research and clinical reporting.