1. Overview

VarSeq VSClinical ACMG

VSClinical is a tool that provides a simple way to leverage all the available evidence for a variant and score it for the potential impact it has on a disorder. The available evidence can be categorized into groups which includes considerations for gene function/phenotype association, variant segregation in a family, results of running variants through prediction algorithms or their presence in databases, but also utilizing previous discoveries you yourself have made for any variant.

This collection of evidence is then linked to 33 criteria that the user can efficiently assess in a streamlined effort. These criteria then are aggregated and provide the basis for the final classifications of pathogenic, likely pathogenic, uncertain significance, likely benign or benign. When considering the amount of available evidence and requirements for eventually classifying variants, this process can become complex and difficult to master. Fortunately, VSClinical is a solution to this complexity for a number of reasons.

Pathognic Scale

Figure 1-1: Pathogenic weighting scale.

VSClinical provides a means of simplifying not only the process of scoring and classifying variants, but also provides both a simple yet sophisticated means of presenting all evidence and criteria visually.

As you work through the classification process, you will be presented with questions you are left to answer to connect the evidence to the best criteria, but VarSeq also computes recommended answers while providing all the supporting evidence for each recommendation.

Pathognic Chart

Figure 1-2: Pathogenic classification results.

One major concern for the process of answering these evidence-based questions and selecting the appropriate criteria is the repeatability of the resulting classification. A possible overlooked issue when manually going through the guideline process is the impact of fatigue. VSClinical removes all the variability and is easy to learn! Through VarSeq’s intuitive workflow, any user not well versed in the ACMG guidelines can be brought up to speed rapidly and produce consistent results. Moreover, we have even implemented a capability of having multiple users make individual blind evaluations, which then can be compared to determine if multiple evaluations have consistent classifications. It is also worth mentioning that despite the application of a simplified workflow, the user can really deep dive into any of the supporting evidence to further clarify the variants impact/classification.

Another advantage of getting new users up-to-speed is that the high workload of assessing variants is streamlined and less users can do more. On top of this, our team works to incorporate new developments to the guideline process, so you don’t have to.

This is a simple interpretation into the immense power behind the VS clinical ACMG workflow, and we have several other resources/publications that can shed more light on the content, but for now let’s focus on looking at an example workflow.