From uncertain to certain—how to proceed with variants of uncertain significance

Abstract With the increased next generation sequencing (NGS) based genetic diagnosis due to technological boon, the biomedical world is getting a substantial number of single nucleotide variations (SNVs) every day along with other genetic variations. The detected SNVs may or may not have clinical significance. Based on different levels of study, these SNVs are categorized either as disease associated or not disease associated. However, there exists another category called as “uncertain” where the scientific literature has scanty of data. These “uncertain” or “variants of uncertain significance (VUS)” has become the greatest challenge for the diagnostic fraternity since no specific decision can be taken by them for the persons carrying the VUS. Therefore, there exists a huge knowledge gap that needs to be addressed for better patient care. The present study aims to find out the possible ways of investigation that may help in reducing this knowledge gap so that decisive approaches can be made against VUS for better and accurate patient care.