Predicting the Effect of Variants of Unknown Significance in Molecular Tumor Boards with the VUS-Predict Pipeline

Precision oncology utilizing molecular biomarkers for targeted therapies is one of the hopes to treat cancer. The availability of patient specific molecular profiling through next-generation sequencing, though, increases the amount of available data per patient to an extent that computational support is required to identify potential driver alterations for targeted therapies and rational decision-making in molecular tumor boards (MTBs). For some genetic variants evidence-based drug recommendations are available in public databases, but for the majority, the variants of unknown significance (VUS), this clinical information is missing. Additionally, for most of these variants no information about the functional impact on the protein is accessible. To acquire maximal functional evidence for VUS, the VUS-Predict pipeline collects estimations about the effect of a VUS by integrating multiple pre-existing tools. Pre-existing tools implement different approaches for their predictions, which are summarized by our newly developed tool with a common score and classification in neutral or deleterious variants. The primary tools are chosen based on their sensitivity and specificity on well-known variants of the transcription factor TP53. Resulting negative and positive predictive values are used to calibrate the VUS-Predict pipeline. Further, the pipeline is evaluated using data from public cancer databases and cases of the MTB in Göttingen, both also in comparison with the ensemble method REVEL. The results show that VUS-Predict has clear advantages in a clinical setting due to clear and traceable predictions. In particular, VUS outperforms REVEL in the real-life setting of a MTB. Likewise, an evaluation on variants of public cancer databases confirms the good results of VUS-Predict and shows the need for a reliable gold standard and unambiguous results of the tools under test.