VSClinical allows for the clinical interpretation of variants based on ACMG & AMP Guidelines

ACMG Guidelines

The VSClinical guided workflow enables following the American College of Medical Genetics (ACMG) guidelines used to identify and classify causal variants for inherited disease risk, cancer predisposition and the diagnosis of rare diseases.

ACMG Guidelines Implemented

The ACMG/AMP joint guidelines for variant interpretation provide a set of criteria to score variants and place them into one of five classification tiers. Following the guidelines requires deep diving into the annotations, genomic context and existing clinical assertions about every variant. VSClinical provides a tailored workflow to score each relevant criterion while also providing all the bioinformatic, literature and evidence from clinical knowledgebases to assist in the scoring and interpretation process.

Accelerated Interpretation

VSClinical is designed to allow variant scientists to efficiently process variants. It focuses on the optimal organization and presentation of the ACMG guidelines criteria as questions with supporting evidence and suggested answers. Previous classifications are automatically brought in, focusing effort on the set of novel variants that need to be scored for the first time. Most novel variants will be classified as benign or likely benign, and VSClinical is organized to quickly identify and classify these variants.

Variant Knowledgebase

The work done in your lab to classify variants will be automatically included in future analyses. As the number of samples processed increases, the number of variants requiring classification will be reduced as well as sample turn-around time. Previously classified variants will be marked with their last evaluation date, allowing them to be accepted in the context of the current sample without extra analysis time. If some critical external data surrounding that variant has changed since it was last evaluated, a flag will be raised to re-evaluate it in the updated context.

Automate Classification

While a final classification of a variant requires the manual inspection of the sample’s clinical details, published literature and the content of existing related clinical interpretations, many attributes of a variant and criteria from the ACMG guidelines can be auto-computed with bioinformatic algorithms and specially curated annotation sources. The ACMG auto-classifier algorithm can reduce the complexity of your annotation and filtering process, helping remove benign variants while highlighting potential pathogenic variants.

Standardize Lab Workflow

Any complex process leaves a lot of room for variation of execution by different lab personnel. VSClinical provides a guided workflow that reduces the amount of subjectivity to the variant classification and interpretation process. Standardized questions, automatically computed evidence, and historical context provides the framework for arriving at the final classification consistently and reproducibly.

Learn as You Go

New variant scientists will be able to start classifying variants with confidence using VSClinical’s integrated documentation and best practice excerpts. The guided workflow includes contextual explanations and descriptions of the specialized data sources and evidence brought in to answer scoring questions. We have carefully curated the published literature on ACMG guideline best practices, adaptations and clarifications.

AMP Guidelines

As an optional add-on, VSClinical can follow the Association for Molecular Pathology (AMP) guidelines used for performing targeted cancer gene panel tests popular in molecular pathology labs to report significant biomarkers of clinical utility in precision medicine.

AMP Guidelines Implemented

The AMP guidelines for the interpretation of somatic variants provide a set of best practices for evaluating and reporting variants for cancer genomic testing. VSClinical provides a guided workflow for following these best practices, including evaluating the clinical evidence for a reportable biomarker using the AMP Tier evidence levels. VSClinical provides a tailored workflow for interpreting and reporting small variants as well as CNVs and fusions.

Jump-start Reports With CancerKB

New biomarkers of oncogenic somatic variants, CNVs or fusions will automatically have gene, biomarker and clinical evidence of therapeutic, prognostic and diagnostic response filled in for many common cancers and genes with the professionally curated Golden Helix CancerKB. In many cases, the report will be jump-started with useful genomic background content and well-established clinical evidence. Interpretations include numerous citations, all of which are aggregated in the appendix of the clinical report.

Standardize Lab Workflow

Any complex process leaves a lot of room for variation of execution by different lab personnel. VSClinical provides a guided workflow that reduces the amount of subjectivity to the variant classification and interpretation process. Standardized questions, automatically computed evidence, and historical context provides the framework for arriving at the final classification consistently and reproducibly.

Interpretation Knowledgebase

The work done in your lab to interpret biomarkers will be automatically be reused in future samples. As the number of interpreted biomarkers increases, the number of novel interpretations of clinical evidence will be reduced as well as sample turn-around time. Relevant interpretations done in different tumor types are displayed as reference and as supporting evidence for the current interpretation.

With ACMG For Germline

Variants selected as suspected or confirmed germline in origin follow the complete ACMG guidelines for assessing and report the variants Pathogenicity. Along with a recommendation and auto-computed classification, the ACMG guidelines criteria are presented with supporting bioinformatic evidence and reasons for suggested answers. A separate germline interpretation catalog saves and automatically applies any previous classifications of a variant seen in other samples.

Automate Classification

Evaluating a novel or infrequently observed somatic variant first requires a though classification of the variants impact on the gene and its ability to activate an oncogene or deactivate a tumor suppressor gene. VSClinical implements a somatic auto-classifier that provides immediate feedback on the potential of newly added variants to be Oncogenic. The classification system includes numerous variant-type specific scoring criteria that can be manually reviewed and adjusted.

Use Cases

Whether testing for cardiomyopathy or other Mendelian genetic disorders highly penetrant pathogenic variants, the ACMG guidelines provides a structured set of criteria for evaluating the evidence that a given detected NGS variant is pathogenic for a specific disorder. Along with supporting bioinformatic evidence and the auto-classifier recommendations, the VSClinical interface provides rich integration with ClinVar and the published classifications provided by previous labs that are for not only the exact variant being reviewed, but also any other variant impacting the same amino acid.
BRCA1 and BRCA2 testing can now be provided by any NGS testing lab with commercially available target capture kits the ACMG guidelines support of VSClinical. Other cancer risk genes often make up these kits and each one is evaluated with the auto-classifier using the full catalog of tens of thousands of variants in ClinVar classified for hereditary cancer risk.
Rare Mendelian diseases can be efficiently diagnosed with exome trio workflows and even targeted gene panels for suspected conditions. VSClinical’s ACMG workflow provides the rich details needed to confirm whether a candidate variant in the causal Pathogenic variant of a rare disease patient. Along with supporting bioinformatic evidence and the auto-classifier recommendations, the VSClinical interface provides a rich environment for discovering and evaluating the published papers that provide clinical and functional evidence for a given test.
With the advent of drugs that target specific molecular functions that drive individual’s cancer, the use of NGS gene panel testing in oncology has taken off to provide the best course of treatment for cancer patients. The AMP guidelines for the reporting and interpretation of somatic variants provide guidelines not only for the evaluation of clinical evidence, but also for the structure and contents of such NGS gene panel reports. VSClinical provides an efficient workflow to support the creation of rich and compressive clinical reports that interpret the detected somatic variants and the applicable targeted molecular therapies for patient’s tumor type.

Recommended Learning Materials

We have a variety of materials for anyone interested in the industry or our software solutions. Here are some of our recommended materials for you to check out related to VSClinical!

Other Resources

Explore a clinical workflow in VarSeq or follow along with a tutorial!

VarSeq Viewer:
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Introduction to VarSeq:
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Try VSClinical for Free

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Technical Specifications

GENERAL PURPOSE HARDWARE REQUIREMENTS

4 GB of RAM

Multicore CPU

100GB of space available for annotations and projects

ADVANCED AND WHOLE GENOME WORKFLOW HARDWARE REQUIREMENTS

If you are working with whole exomes or genomes, especially if or hundreds to thousands of samples, we suggest a high-memory configuration and plenty of storage capacity:

16GB+ of RAM (32GB for Servers)

8+ CPU Cores

1TB of space available for annotations and projects

OPERATING SYSTEMS

The following operating systems are supported:

64-bit Windows 7 or later

Linux Ubuntu 14.04 or later (64-bit only)

Linux RHEL 7 or later, or equivalently CentOS 7 or later (64-bit only)

Mac OS X 10.10 or later

PROXY SETTINGS, FIREWALLS AND ANTIVIRUS

Golden Helix VarSeq and SVS can be configured to access the internet through a SOCKS5 or HTTP/HTTPS Tunneling Proxy. Go to Tools -> Proxy Settings… to configure.

The software only needs to make outgoing connections on standard HTTP/HTTPS ports and protocols. If a local firewall is installed that prevents these types of outgoing connections (this is very uncommon), firewall rules will need to be created to whitelist the software.

Note we have run into numerous issues where aggressive anti-virus programs prevent the product from performing normal operations such as opening files and logging in. You may need to whitelist Golden Helix executables or disable these tools to perform your analytics.