Reclassifying VUS

When we ask people what they value most about VarSome, the most common response is “the classifiers”. In building our germline and somatic variant classifiers, we automated a very time-consuming and labor-intensive process. We apply the relevant interpretation guidelines in a clear and transparent way, and present the evidence that triggers rules leading to the classification of the variant. Given that this is all made possible by some very sophisticated AI and integration algorithms, it might surprise some of you to know that at Saphetor, we have an in-house variant curation team.

This is because manual curation of variants is still the gold standard when it comes to interpretation. Much in the same way that Sanger sequencing is still the gold standard when it comes to accurate DNA sequencing - it takes time, but is highly accurate. We apply manual curation specifically to variants of uncertain significance (VUS). In particular, VUS variants in genes that are associated with diseases of greatest interest to the research community, as well as genes known for their actionability and their impact on clinical practice. The goal of the curation team is to reduce the number of VUS by reclassifying them based on manual review of all available evidence.

From left to right: Athina Mourtzaki, Asimina Andritsou, Ioannis Liopetas, and Alma Mudrov

The Saphetor curation team applies specialist expertise and critical thinking when manually reviewing variants. They review information supplied by the VarSome community, such as publications linked as relevant to a variant, as well as any associated user comments. They also work through large amounts of evidence found in the scientific literature, looking for functional studies to establish the molecular basis of a change in gene function that could result in the observed condition, as well as evaluating other cases in which the variant in question has been reported. This can then be integrated with VarSome’s automated classifiers to trigger rules that may result in a reclassification of a variant that was previously presented as VUS providing supporting evidence for a more accurate prediction of variant pathogenicity.

Our curation team follows Standard Operating Procedures for curating variants based on guidelines published by the American College of Medical Genetics and Genomics (ACMG) and ClinGen’s recommendations, including their Variant Curation Expert Panels Protocol (VCEP). The curation team is also involved in curating specific variant datasets for validation purposes of our algorithms. At the time of writing, over 12 000 variants have been manually classified in the VarSome database. 

If you would like to know more about how you could be working with our curation team and make the most of VarSome Clinical, let us know at sales@VarSome.com to set up a call.

About Saphetor SA

Saphetor SA, is a global precision-medicine company dedicated to large-scale identification and interpretation of human genetic variants by leveraging proprietary algorithms and expert domain knowledge.

Saphetor is the creator of VarSome, a suite of intuitive and data-driven bioinformatics solutions both for clinicians and researchers. VarSome.com professional community and search engine is freely accessible, featuring a widely-recognized community-driven knowledge base that enables flexible queries across more than 140 genetic and genomic data resources.

VarSome Premium and VarSome Clinical are professional editions of VarSome with powerful functionality and further sophisticated data-mining and analysis tools. VarSome Clinical is a CE-IVD-certified and HIPAA-compliant platform allowing fast and accurate variant discovery, annotation, and interpretation of NGS data for whole genomes, exomes, and gene panels, which helps clinicians reach faster and more accurate diagnoses and treatment decisions for genetic conditions. VarSome can also be integrated into existing in-house pipelines via VarSome API through cloud-based or on premises installations.