VUSVista: Enhancing the Curation of Variants of Uncertain Significance

Background The increased demand for genomic sequencing has consequently led to a rise in the number of Variants of Uncertain Significance (VUS), which are classified as such due to insufficient evidence to determine their pathogenicity. VUS lead to incomplete diagnosis for patients, potentially causing anxiety due to the uncertainty associated with VUS and resulting in suboptimal management. Results We developed a software, VUSVista, for organised and semi-automated VUS curation. It offers American College of Medical Genetics and Genomics (ACMG) criteria management, external database references, standardised Human Phenotype Ontology (HPO) terms for sample phenotypes, links between variants and pseudonymised samples as well as audit trails. VUSVista automatically checks for updates to ClinVar’s germline classification entries of recorded VUS and searches for newly released publications referencing its VUS using Lit-Var 2.0. Users are notified whenever a ClinVar entry is updated or a relevant publication is found, helping them stay informed about new scientific discoveries. Assessing the significance of this new evidence may lead to VUS reclassification through VUSVista. One-to-one sessions and a focus group were conducted with medical laboratory scientists and a senior pharmacist to validate the system. Conclusions Overall, VUSVista facilitates VUS curation and reclassification, increasing the likelihood that patients receive a comprehensive diagnosis and the most appropriate treatment. Its implementation is publicly available on GitHub ( https://github.com/estherspiteri/VUSVista ).