Clinical Variant Analysis: Part I

         February 19, 2019

Clinical Variant Analysis – Applying ACMG Guidelines to Analyze Germline Diseases

The clinical interpretation of genetic variants is time-consuming and requires strict attention to detail. Clinicians must thoroughly review any variants that could potentially cause disease using a complex set of guidelines. There are guidelines for the interpretation of variants relating to hereditary risk, germline diagnostics issued by the American College of Medical Genetics (ACMG), which are nationally and internationally recognized.

Currently, the global next-generation sequencing (NGS) market is valued at USD 5.70 billion and is expected to reach USD 16.35 billion by the year 2024. This represents a compound annual growth rate (CAGR) of 19.2%0. Contributing to this growth are the following critical factors:

  1. An increase in the number of disease treatment options, accompanied by the adoption of precision medicine & molecular diagnostics
  2. Advancements in NGS platforms, with sequencers providing increased throughput and improved data quality
  3. A decline in NGS capital requirements – while the sequencing technology itself improves, there are reduced capital requirements across multiple sequencing platform providers
  4. Changes in the regulatory environment, with an increase in acceptance of utilization of NGS-based tests in the clinic
  5. Changes in reimbursement, with payors increasingly willing to pay for these tests
  6. Funding for large-scale sequencing projects from both government & private sources

These developments constitute a significant dilemma for the industry. We have on one hand a labor-intensive diagnostic process that requires expertise and attention to detail, while on the other hand a rapidly growing demand for NGS-based tests. Clinical laboratories in this space can expect to double their workload within the next four years, with similar if not greater growth anticipated beyond that. At the same time, there is already a shortage of clinical experts in the field of genetics with specific expertise in the NGS area. Automation is the only way to solve this dilemma.

The process of final variant classification and reporting often requires adjudicating multiple lines of evidence, following decision trees and evidence weighing systems. Automation of this process will help to eliminate the problems associated with human error and individual subjectivity. In addition, automation of the informatics and providing guided workflows will reduce the time and effort required for molecular pathologists and medical geneticists to sign off on clinical reports. Over the last few years, we have had extensive dialogues with users (our customers) who work in this clinical setting, to identify the processes, optimized workflows, and challenges, which led up to the initial launch of our VSClinical product. The key value of VSClinical includes:

  • Delivery of consistent, high-quality interpretations: Clinical variant interpretation is a complex task. The person conducting the analysis must be well trained and have deep domain knowledge. In addition, over the course of a busy workday, maintenance with a high level of attention to detail is required. The quality of the analysis has to be equally excellent regardless of when the work is being conducted – be it at 8:00 AM in the morning, at 1:30 PM right after lunch, or well into the evening hours.
  • Providing a framework for newer, less experienced clinicians: As the volume in a clinical laboratory ramps up, inevitably there will be a need to bring additional staff up to speed in conducting the analytics. Using an early version of VSClinical, we were able to demonstrate that this solution can be tremendously helpful in this context. Our product provides a framework that supports less experienced analysts so that they can confidently conduct high-quality work in this space. In many instances, our product provides clear, specific guidance on how to answer certain questions (and if in doubt, the trainee can still engage with more senior staff members in the lab when necessary). Overall, VSClinical has the potential to significantly reduce the ramp-up time it takes to bring new staff up to speed in the clinical interpretation of variants.
  • Staying abreast of new developments: We as a company invest a lot of time directly engaging with the community of end-users, attending conferences, engaging with our clients, and consulting with outside experts as part of our product development process. Based on this ongoing feedback, we regularly update the software to ensure that it reflects state-of-the-art variant analysis and interpretation. This is reassuring to clients, who would face otherwise the same burdensome process to stay abreast of new developments, but who don’t have the time and resources to perform this leg work.

The widespread implementation of NGS technologies has produced a vast number of variants to analyze and categorize. There are numerous data sources containing a wealth of knowledge about the clinical relevance of variance. In addition, there is a wide array6 of algorithms that help to assess how the presence of a variant functionally impacts a particular gene and the associated protein. We are long past the point where these types of analytics can be conducted manually. The first implementation of our clinical variant analysis solution, VSClinical, is focused on the guidelines issued by the American College of Medical Genetics and Genomics (ACMG). They focus in on how to systematically assess the clinical variants of germline mutations.

This eBook will discuss the inner workings of the ACMG guidelines in 5 major parts:

The American College of Medical Genetics and Genomics (ACMG) developed guidance for the interpretation of sequence variants. The rapidly changing advances in sequence technology in the ten years after the publication of the first guidelines led to a major revision of the guidelines in 2015. This eBook is referencing primarily the key paper on this subject published by Richard et al. in 2015 (1). By adopting and leveraging NGS, clinical laboratories are now performing an ever-increasing catalog of genetic tests covering genotyping, single genes analysis, gene panels, clinical exomes, genomes, transcriptomes, and epigenetic assays to detect the underlying causes of genetic disorders. By virtue of the increased complexity, this expansion in genetic testing has been accompanied by new challenges in the interpretation of sequence variants. The recommendations primarily apply to the breadth of 7 genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. The report recommends the use of specific standard terminology to describe variants identified in genes that cause Mendelian disorders:

  • Pathogenic
  • Likely Pathogenic
  • Uncertain Significance
  • Likely Benign
  • Benign

In this eBook, we will look at all relevant criteria outlined in the guidelines and how they are being combined properly. Moreover, I will show you how these types of analysis are conducted in VSClinical. If you wish to continue reading this eBook, I invite you to download a complimentary copy of my eBook. You can do so by clicking the button below.

I hope you enjoy and if you have any questions, please feel free to email me at

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