ACMG-Based Variant Classification with VSClinical

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Golden Helix is a global bioinformatics company founded in 1998 that provides software for variant annotation, filtering, and interpretation. Their flagship products are VarSeq Suite and VSClinical. VarSeq Suite allows for powerful variant filtering and annotation using curated public databases and premium annotations. VSClinical streamlines variant classification using American College of Medical Genetics and Genomics guidelines through a four-phased workflow involving variant filtering, evidence assessment, classification, and reporting. It provides consistent results and reduces learning curves for users. Golden Helix has over 400 customers globally and their software is cited in thousands of peer-reviewed publications.

ACMG-Based Variant Classification with
VSClinical
Eli Sward, Ph.D.
Field Application Scientist
20 Most Promising Biotech
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NIH Grant Funding Acknowledgments
• Research reported in this publication was supported by the National Institute Of
General Medical Sciences of the National Institutes of Health under:
• Award Number R43GM128485-01
• Award Number R43GM128485-02
• Award Number 2R44 GM125432-01
• Award Number 2R44 GM125432-02
• Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005
• PI is Dr. Andreas Scherer, CEO Golden Helix.
• The content is solely the responsibility of the authors and does not necessarily
represent the official views of the National Institutes of Health.

Who Are We?
Golden Helix is a global bioinformatics company founded in
1998
Filtering and Annotation
ACMG Guidelines
Clinical Reports
CNV Analysis
Pipeline: Run Workflows
Variant Warehouse
Centralized Annotations
Hosted Reports
Sharing and Integration
CNV Analysis
GWAS | Genomic
Prediction
Large-N Population
Studies
RNA-Seq
Large-N CNV-Analysis

Cited in 1,000s of Peer-Reviewed Publications

SIMPLE, SUBSCRIPTION-
BASED BUSINESSMODEL
o Yearlyfee
o Unlimitedtraining&support
SOFTWARE ISVETTED
o 20,000+ usersat 400+ organizations
o Quality&feedback
DEEPLY ENGRAINED IN
SCIENTIFIC COMMUNITY
o Give backto thecommunity
o Contributecontentandsupport
INNOVATIVESOFTWARE SOLUTIONS
o Cited in1,000s ofpublications
When you choose Golden Helix,
you receive more than just the software

VarSeq Suite
Simple Flexible Scalable
Variantannotation
filtering, andinterpretation
PowerfulGUIwith
richvisualizations
Repeatable
workflows

VarSeq - Annotations
• Curated Public Databases
o 1kG Phase3 Variant Frequencies
o RefSeq Genes, NCBI
o ClinGen Dosage Sensitivity
Mapping
o dbNSFP Functional Predictions
• Lock down version
• Notifications for track updates
• Premium Annotations:
o CADD
o COSMIC
o Conservation Scores
o SIFT/PolyPhen2
o Splice Site Algorithms
o OMIM phenotypes and Genes
o dbSNP
o ExAC
o ClinVar
o CIViC

VSClinical - Value
• Consistent results
• Shorten learning curve
• Staying abreast of new
developments

VSClinical - ACMG Rules for Classification
Richards et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics
and Genomics and the Association for Molecular Pathology. 2015, Genet Med 17: 405-424.
Pathogenic Likely Pathogenic Uncertain
Significance
Likely Benign Benign
Rules Presented in
VSClinical

VSClinical – Four-Phased Workflow
1. Filter and select variants for evaluation
• Follows existing VarSeq filter workflow
2. Assess all evidence for variant
• Presented in VSClinical interpretation hub
3. Develop final classification
• Directly follows ACMG Guidelines
‐ 33 criteria for evaluating evidence
‐ 5 possible classifications built from
criteria
‐ Include caveats and discussion for
evaluating criteria in different contexts
• Develop and catalog variant interpretation
4. Include interpretation in final clinical
report
Benign
Pathogenic
Uncertain Significance

The so-called “next-generation” sequencing (NGS) technologies allows us, in a short time and in parallel, to sequence massive amounts of DNA, overcoming the limitations of the original Sanger sequencing methods used to sequence the first human genome. NGS technologies have had an enormous impact on biomedical research within a short time frame. This talk will give an overview of these applications with specific examples from Mendelian genomics and cancer research. #h2ony

The ClinGen Sequence Variant Interpretation Working Group: Refining Criteria ...

Human Variome Project

A key barrier to the efficient clinical utilization of genome sequence data is the lack of a systematic approach for interpreting the pathogenicity of genetic variants, with resultant discordance among laboratories and researchers in classification. The ClinGen (Clinical Genome) Project has been funded by the United States National Institutes of Health with a goal of maximizing the clinical relevance of results from genetic testing. ClinGen has established a Sequence Variant Interpretation (SVI) Working Group to refine and standardize the approach to pathogenicity classification. Recently the American College of Medical Genetics and Genomics (ACMG) published guidelines [1] that emerged from a workgroup that represented the expert opinion of clinical laboratory directors and genetics clinicians. These guidelines were developed to help clinical laboratories that report results from sequencing of single genes, panels, exomes, and genomes. The ClinGen SVI has set short term and long term objectives for advancing the field of pathogenicity interpretation using the ACMG framework as a starting point. There is consensus within the field that correct classification of variants requires integrating multiple lines of evidence, including, clinico-pathologic, epidemiologic, bioinformatics (in silico), and in vitro data. How best to combine them is unclear. The ACMG framework described different categories of evidence and assigned preliminary assessments of what comprises weak or strong evidence favoring a variant’s pathogenicity or neutrality and preliminary rule- based algorithms of how to combine evidence. In the short term, the ClinGen SVI has set up sub-committees to apply more precision in defining criteria for pathogenicity and what comprises strong and weak evidence. In the long term, the ClinGen SVI looks to transition from qualitative descriptions to a quantitative system that can assign an empirically derived probability of pathogenicity for each variant. Preliminary analyses suggest that there will be general rules that apply to all genes, as well as specific approaches for different genetic disorders. Well characterized databases of variants for each genetic disorder will be critical to the process. Funded by the National Human Genome Research Institute through the following three grants: U41 HG006834-01A1, U01 HG007437- 01, U01 HG007436-01, and by the National Cancer Institute through contract HHSN261200800001E. Reference: 1. Richards S, Aziz N, Bale S, et al. Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine2015;17(5):405-424.

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Clinical Genetic testing requires a complex analysis using the totality of our knowledge about the clinical relevance of a variant and a gene. This includes bioinformatic evidence as well as clinical evidence. The ACMG Guidelines provided a framework in which to score variants based on this evidence, and while some of those scoring criteria require close consultation of the clinical context for a given patient, much of it can be automated. In this webcast, we review how VSClinical automates the ACMG scoring guidelines while integrating the collective lab expertise from previously classified variants and preferences about genes. We will cover: Using the ACMG Auto Classifier as part the filtering strategy for gene panels and trio workflows How gene preferences such as the default transcript, inheritance model, and disorder are updated and saved from VSClinical and used in all future analysis How the per-variant recommendation engine builds on the auto-classification with descriptive reasons for answering each criterion yes or no Using the auto-interpretation to present the evidence for all scored criteria in a human-readable paragraph Working with VSClinical’s self-learning knowledgebase that incorporates previously classified variants and genes inform the interpretation of new variants!

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Next-generation sequencing (NGS) is a driving force for numerous new and exciting applications, including cancer research, stem cell research, metagenomics, population genetics, medical research and single cell analysis. While NGS technology is continuously improving, library preparation remains one of the biggest bottlenecks in the NGS workflow and includes several time-consuming steps that can result in considerable sample loss and the potential to introduce handling errors. Moreover, conducting single-cell genomic analysis using NGS methods has traditionally been challenging since the amount of genomic DNA present in a single cell is very limited.

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VarSeq is a tertiary analysis platform that allows users to filter and annotate NGS sequencing data to identify clinically relevant variants. Following this workflow, VSClinical can then be used to automate both germline and somatic variant analysis in accordance with the ACMG and AMP guidelines by using a variety of functional prediction models and clinical and reviewer-based annotations. Once variant or biomarker interpretations are completed, they can be rendered in a customizable clinical report and stored in an internal assessment catalog as an internal variant database repository. Together, implementation of VSClinical will promote increased lab throughput as well as accuracy and compliance with the ACMG and AMP guidelines, which in turn can save time and money. To show the capabilities of our software, this webcast will provide a demonstration of how to use VarSeq and VSClinical for the evaluation of both germline and somatic variants in accordance with the ACMG and AMP Guidelines. In this webcast, we will cover: - Filter logics for germline and somatic variants and selecting them into the VSClinical interface - Capabilities of functional prediction and splice site algorithms for edge case variants - The functionality of changing the clinically relevant transcript on variant interpretation - Rendering a clinical report with germline and somatic variants with the inclusion of clinical trials

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The common approaches to detecting copy number variants (CNVs) are chromosomal microarray and MLPA. However, both options increase analysis time, per sample costs, and are limited to the size of CNV events that can be detected. VarSeq’s CNV caller, on the other hand, allows users to detect CNVs from the coverage profile stored in the BAM file, which allows you to utilize your existing NGS data and perform the analysis all in one suite. Coupled with this innovative feature is the ability to annotate CNV events against a variety of databases, and by incorporating our VSClinical AMP workflow, we can now assess CNVs as potential biomarkers. Most importantly, Golden Helix CancerKB is an AMP workflow feature that provides expert-curated biomarker interpretations, including those for common somatic CNVs, that will streamline the analysis time and report generation. In this demonstration we will cover: Setting up the VS-CNV caller using BAM files from whole exome data Filtering down to high quality, high confidence CNV events Annotating CNVs using publicly curated catalogs and databases Adding clinically relevant CNVs to the VSClinical AMP workflow Utilizing Golden Helix CancerKB to obtain expert-curated interpretations Showing updated features and polishes to the software Together, VarSeq incorporates the ability to accurately call and annotate CNVs and evaluate germline and somatic mutations according to the ACMG and AMP guidelines, respectively. This webcast demonstration will provide insight into these best practice workflows and will hopefully show you how you can implement this top-quality software into your pipeline solution.

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Anyone handling NGS data understands the constant issue of not only storing all the variant data but also the difficulties in querying through a massive dataset. VarSeq has grown an excellent reputation for being a powerful filtration and annotation engine for NGS data. Tightly coupled with VarSeq is our genomic repository solution, VSWarehouse. VSWarehouse provides a means of storing all variant cohort data as well as rapid querying capabilities to quickly navigate through the, potentially, millions of variants you may amass over time. Just as important is the ability to store this data; users can find relief that VSWarehouse is designed to be installed behind a private network to ensure the protection of all genomic data. Join us in this webcast as we explore the key value points, usability, and direct scalability of VSWarehouse. What will you learn in this webcast? From VSWarehouse, how to access the browser to investigate: -Querying updated clinical evidence against an existing variant cohort -Filtering through stored projects for all relevant variant data -Accessing the administrator-level permissions management site From VarSeq, how to leverage variant data in VSWarehouse to: -Filter out common variants in the store cohort -Annotate and plot VSWarehouse content in the VarSeq project -Utilize congruent assessment catalogs for storing variant classifications uniformly for all users

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A User’s Perspective: Somatic Variant Analysis in VarSeq 2.3.0

Golden Helix

VarSeq 2.3.0 facilitates the evaluation of a multitude of somatic genomic variations with a more refined user interface to streamline variant evaluation. Our recent webcasts have shown the full range of these newly developed upgrades: VarSeq 2.3.0: Supporting the Full Spectrum of Genomic Variation VarSeq 2.3.0: New TSO-500 and Genomic Signature Support in VSClinical AMP Now, we are showing it all in action from the user’s perspective. This webcast will provide a comprehensive demonstration of performing somatic variation analysis and reporting. We will review how to use workflow automation to expedite the NGS project creation process and report rendering. We will also demonstrate the streamlined capture of knowledge during variant evaluation by leveraging our clinical expert-curated interpretations with the Golden Helix Cancer Knowledge Base (CancerKB). We hope you will join us to see VarSeq 2.3.0 from a user’s perspective, covering: -Somatic variant workflows: necessary algorithms and filtering strategies -Import of all relevant biomarker and genomic signatures data from TSO-500 -Review content and value of clinically curated interpretations and treatments with CancerKB -Interpretation of structural variants in the VSClinical AMP Guidelines workflow -Workflow automation with VSPipeline

VarSeq 2.4.0: VSClinical ACMG Workflow from the User Perspective

Golden Helix

Earlier this year, we released VarSeq 2.3.0 which brought massive updates to our VSClinical AMP interface, such as enhanced capabilities for automation and analysis of structural variants in the cancer context. Naturally, we wanted to follow that up shortly with similar advancements to our VSClinical ACMG interface, and also make our customers doing germline variant analysis happy. Our latest software release, VarSeq 2.4.0, was therefore focused on the advancements in VSClinical ACMG, namely support for importing and clinically evaluating structural variants, long read sequencing, advanced automation with evaluation scripts in VSClinical ACMG and end-to-end automation of ACMG workflows with VSPipeline. These new and improved features were discussed in a great webcast by our VP of Product and Engineering, Gabe Rudy, last month. This upcoming webcast by our FAS team will be a user’s perspective on the new features in VarSeq 2.4.0 and VSClinical ACMG and how our tools can precisely and efficiently enable the full spectrum NGS analysis for Mendelian disorders.

VarSeq 2.4.0: VSClinical ACMG Workflow from the User Perspective

Golden Helix

Introducing VSClinical AMP Guidelines: A Comprehensive Workflow for NGS Testi...

Golden Helix

The individualized nature of tumors requires genomic testing for providing the best outcomes for patients. Next-Generation Sequencing enables the detection of small mutations, copy number changes, and common fusions affordably and with high precision. However, the interpretation of these detected variants is arduous without a comprehensive analytical workflow that can incorporate all the bioinformatics and clinical evidence involved in following the AMP guidelines for the scoring and reporting of somatic mutations. Please join us as we reveal the AMP guidelines workflow support in VSClinical. We will cover the entire post-sequencing analytical workflow from FASTQ to clinical report, including: - Apply the AMP Tiers to the available clinical evidence for Drug Sensitivity, Drug Response, Prognostics and Diagnostics Support small mutations (SNPs, InDels) along with CNVs, fusions and wild-types as relevant biomarkers for the reporting of clinical evidence - Develop a lab-specific knowledgebase of interpretations that allow maximum re-use of interpretations and descriptions from one patient to the next - Leverage the built-in Golden Helix CancerKB interpretation knowledgebase that covers many common genes and biomarkers - When detecting inherited and not somatic variants in a patient, score and classify them using the ACMG guidelines and report as secondary germline findings - Use the Oncogenicity scoring system for evaluating the impact of variants in cancer - Customize your clinical report using Word to reflect your lab's preferences and branding - Building on the success of VSClinical’s ACMG guidelines, the new VSClinical AMP guidelines enables new and existing labs to provide genetic tests for cancer efficiently and with a focus on delivering consistent and accurate results.

Reduce Turn-Around with Enhanced Cancer Annotations and CancerKB Updates

Golden Helix

Annotation sources are constantly evolving, sometimes quite literally overnight. This is especially true in the case of cancer databases. These ever-evolving annotation sources, coupled with increasing research publications, make it difficult to do variant analysis with up-to-date scientific knowledge. With the resources available to an individual clinician or single lab, this may even prove impossible. Fortunately, VSClinical provides access to the most current clinical annotation sources - automating scoring and interpreting variants according to the most recent ACMP and AMPO guidelines. This includes many fast-changing sources such as ClinVar and COSMIC, as well as expert-curated reviews of literature and the latest drug-labeling from regulatory bodies. In this webcast, we demonstrate the automation of a cancer workflow with enhanced cancer annotations for somatic and germline cancer variants: - Golden Helix’s own CancerKB database has been updated to include new interpretations for genes and biomarkers with AMP Tier Level I evidence for drug sensitivity, resistance, diagnostic, and prognostic information. - We feature a new Golden Helix curated annotation source that automates the scoring of TP53 variants with the special rule specifications by ClinGen’s TP53 Expert Panel. - The ClinGen Expert Curated Interpretation of Variants has always been available as an annotation source for VarSeq projects, but now the expert comments and interpretations can automatically be pulled into VSClinical and used for clinical reports. This webcast walks through a hematological-focused cancer workflow that shows off the enhanced cancer annotations and CancerKB updates!

VarSeq 2.3.0: New TSO-500 and Genomic Signature Support in VSClinical AMP

Golden Helix

Precision medicine for cancer is rapidly accelerating because of the development and approval of targeted molecular therapies. These therapies require new genomic biomarkers as an indication for use, and require evaluating additional mutation types that are available in comprehensive genomic profiling assays as well as the small variants detected by Next-Generation Sequencing gene panels. We are excited to announce VarSeq 2.3.0 which will update the VSClinical AMP workflow to meet the growing needs of labs conducting comprehensive genomic profiling (CGP) of tumors. This includes built-in support for the Illumina TruSight Oncology 500 (TSO-500) kit as well as similar kits from other vendors. The VSClinical AMP workflow has also gained native support for the bioinformatic outputs of CGP kits. Join us to learn about comprehensive genomic profiling in cancer, specifically: Evaluation and clinical reporting of genomic signatures such as Microsatellite (MSI), Tumor mutation burden (TMB), PD-L1, Homologous recombination deficiency (HRD) statuses, and more. Built-in TSO-500 import and expandable import capabilities for new genomic data types through the new advanced workflow scripting system. Golden Helix CancerKB updates with report-ready genomic-signature interpretations written for approved therapies as well as gene interpretations for all 500 genes of the TSO-500 panel. In addition, CancerKB scopes have been extended to reference multiple relevant biomarkers in a single interpretation, capture approved therapies at the tumor type level, and include interpretations for clinically relevant negative findings. Expanded clinical trial support to include international trials and the ability to search within proximity of European postal codes. VSClinical is accessing all active studies in AACT/ClinicalTrials.gov wherein users can search and select trials based on relevant drugs, biomarkers, and the geographic distance to the patient or testing site. VarSeq 2.3.0 will deliver powerful capabilities for genomic profiling in cancer, enabling a new level of personalized and effective care for your patients. We look forward to demonstrating these updates and Golden Helix’s continued innovation making the VarSeq Clinical Suite the NGS analysis platform of choice for germline and cancer testing.

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Introducing VarSeq Dx as a Medical Device in the European Union

Golden Helix

A transition period regarding in vitro medical device (IVD) regulation in the European Union (EU) is upon us. The former IVDD regulations are phasing out and IVDR 2017/746 has already taken its place as the acting regulation for IVD manufacturers but also lab developed tests (LDTs) and health institutions. In our upcoming webcast we will talk about the roles and significance of IVDR and ISO 13485 certification for clinical labs and for Golden Helix as a medical device manufacturer. Join us as we will introduce VarSeq 2.6.1 complete with Dx Mode, which offers the use of VarSeq as CE marked medical device. Even more we will also present strategies to facilitate the transition of Golden Helix customers to operate in accordance with IVDR.

VarSeq 2.6.0: Advancing Pharmacogenomics and Genomic Analysis

Golden Helix

In the rapidly evolving field of genomic analysis, staying current with the latest research, data sources, and test advancements is crucial. In this webinar, we review how VarSeq addresses the needs to stay on top of the latest with the release of VarSeq 2.6.0. This release features an exome-optimized workflow for LOH and CNV calling as well as the introduction of VSPGx to produce pharmacogenomic reports for gene panels as well as exomes and genomes. With the recent release of gnomAD v4, we have had many requests for the integration of this large update to the most population frequency source. With VarSeq 2.6.0, the latest version of gnomAD has been integrated into VSClinical and the updated tracks spans beyond variants to cover CNVs and gene scores to update all your workflows to the latest data. In this webcast, we will cover. Improved VS-CNV performance and updated exome analysis workflows. Pharmacogenomics in action: Utilizing VSPGx for exome and genome assessments. gnomAD v4 in practice: Updated automated and manual variant interpretation workflows. Join us for an insightful session on the latest VarSeq 2.6.0 features, bringing you the most up-to-date data and workflows for your genomic analysis.

Introducing VSPGx: Pharmacogenomics Testing in VarSeq

Golden Helix

Inter-individual variability in drug response poses a significant challenge for clinicians, with much of this variability resulting from inherited genetic differences. While the field of pharmacogenomics (PGx) can provide powerful insights into how genomic factors affect drug response, the implementation of PGx testing in the clinic is hampered by the difficulty of translating genetic test results into actionable recommendations. In this webcast, we will discuss VarSeq’s new PGx testing capabilities, including the ability to identify actionable pharmacogenomic diplotypes and generate clinical reports. In this webcast you will learn: -How to identify pharmacogenomic diplotypes and drug recommendations from NGS data. -How to incorporate externally called CNVs and SVs into your PGx annotations. -How to generate customizable PGx reports from these annotations.

Analyzing Performance of the Twist Exome with CNV Backbone at Various Probe D...

Golden Helix

Clinical Whole Exome Sequencing (WES) offers a high diagnostic yield test by detecting pathogenic variants in all coding genes of the human genome. WES is poised to consolidate multiple genetic tests by accurately identifying Copy Number Variation (CNV) events, typically necessitating microarray analyses. However, standard commercial exome kits are limited to targeting exon coding regions, leaving significant gaps in coverage between genes which could hinder comprehensive CNV detection. Addressing the need for comprehensive coverage, Twist Bioscience has developed an enhanced Twist Exome 2.0 Plus Comprehensive Exome Spike-in capture panel with added "backbone" probes. These probes target common SNPs polymorphic in multiple populations and are evenly distributed in the intergenic and intronic regions, with three varying densities at 25kb, 50kb, and 100kb intervals. In this webcast, we discuss the combined efficacy of the backbone-probe enhanced exome capture kit and VS-CNV in identifying known CNVs using the Coriell CNVPANEL01 reference set. This webcast reviews: -The sensitivity rate for the detection of known CNV events at all three probe densities. -The impact of best-practice quality metrics and filters on sensitivity. -How VarSeq’s CNV annotation capabilities can be leveraged to identify likely pathogenic CNVs. -The interpretation of clinically relevant CNVs using VSClinical.

From Panels to Genomes with VarSeq: The Complete Tertiary Platform for Short ...

Golden Helix

From gene panels to whole genome, from short to long-read sequencing, the VarSeq suite is the solution for NGS analysis and reporting in a modern clinical lab. VarSeq handles the spectrum of variant types (SNV, Indel, CNV, Fusions) and provides automated classification and reporting capabilities following the ACMG and AMP guidelines. With our new PacBio partnership, we are more adaptable than ever with creating a spectrum of custom workflows to suit our unique user needs. This webcast will review: -Data analysis scaling from Gene Panel to Genome analysis with VarSeq and VSWarehouse. -Analysis and annotation of SNVs, Indels, CNVs, and fusions. -A close look at a PacBio long-read trio analysis. Come join us for this showcase in modern VarSeq analysis capabilities.

Enhance Genomic Research with Polygenic Risk Score Calculations in SVS

Golden Helix

Golden Helix’s SNP & Variation Suite (SVS) has been used by researchers around the world to do trait analysis and association testing on large cohorts of samples in both humans and other species. The latest SVS release introduces a significant leap in capabilities, with a focus on advanced Polygenic Risk Score (PRS) calculations. PRS has become a fundamental tool in genomic research, enabling the identification of correlations between genotypic variants and phenotypes across large populations. This enhancement is particularly relevant for researchers working on large cohorts and meta-analysis. Please join us as we explore: -SVS Workflow Review: A review of the extensive capabilities of SVS to meaningful insights from large cohorts and association test result datasets -Computing Polygenic Risk Scores: An overview of the PRS capabilities in SVS, including Clumping and Thresholding and creation of multiple PRS models -Evaluating and Applying PRS: Evaluating PRS models in-sample and out-of-sample and applying PRS models to perform trait prediction -Future Implications: Brief exploration of how these advancements in SVS could influence future genomic research. This webcast will explore how SVS facilitates the creation of multiple PRS models from large-scale genomic data, such as those obtained from extensive cohort studies or comprehensive meta-analyses. Join us to discover how these latest updates in SVS are supporting large-scale genomic research.

VarSeq 2.5.0: Empowering Family Planning through Carrier Screening Analysis

Golden Helix

Over the past 50 years, partners with potential genetic risks have sought advanced genetic testing to guide family planning decisions. Carrier screening is a valuable tool in genetics and reproductive medicine that helps individuals and families make informed choices about family planning and reduce the risk of passing autosomal recessive or X-linked genetic disorders to their children. Several carrier screening panels are available for Next-Generation Sequencing platforms, ranging from those targeting prevalent disorders to expanded ones covering various inherited conditions. Since NGS offers an affordable, high-throughput solution, carrier screening has become a common practice in healthcare systems. We are excited to announce that VarSeq and VSClinical now support a multi-sample carrier screening workflow. VarSeq 2.5.0 unlocks the ability to: -Filter variants between samples and identify genes in which a variant from each partner sample is present. -Apply the ACMG Carrier Screening gene panel or generate customized carrier screening panels to include in your analysis. -Evaluate partnered samples side-by-side in a single VSClinical evaluation. -Generate a combined sample clinical report that includes reproductive risk calculations for the most prevalent autosomal recessive and X-linked diseases.

Identifying Oncogenic Variants in VarSeq

Golden Helix

The interpretation of somatic variants can be a challenging process. While AMP Guidelines provide detailed rules for accessing the clinical evidence associated with a specific variation, they do not specify criteria for determining if a variant is likely to be a driver mutation, which generates functional changes that enhance tumor cell proliferation. In this webcast, we will discuss a new VarSeq algorithm for estimating the oncogenicity of a variant. This will include a deep dive into our oncogenicity scoring system and a discussion of the various criteria used to distinguish driver mutations from benign variations and variants of uncertain significance. What you will learn in this webcast: -How to use the scoring algorithm to identify variants with evidence of oncogenicity -Which criteria are used to assess a variant's oncogenicity -How to evaluate the oncogenicity of a variant in VSClinical

Best Practices for Validating a Next-Gen Sequencing Workflow

Golden Helix

Validating an NGS workflow is an iterative process that begins with collaboration with personnel and planning protocols for the entire workflow from sample preparation, sequencing and variant calling, all the way to data analysis and reporting. At Golden Helix, while we do not provide pre-validated black-box workflows, we provide our customers with support to validate workflows in a transparent manner, and assist them in reaching production deadlines. This webcast will be led by members of our Field Application Scientist team, and we will explore some of the best practices for NGS workflow validation that we have observed and helped to implement based on real-world examples from our customer base. Key topics for discussion will include: Sample preparation and collection of adequate case/control data Designing a robust workflow with special considerations for single versus family analyses and phenotypic considerations Generating the desired output for clinical or other reports Real world NGS workflow validation strategies Tune in for tips and strategies that you can deploy when designing and validating your NGS workflow.

2023 Innovation Awards Winner, Dr. Muthukumaran

Golden Helix

The Wide Spectrum of Next-Generation Sequencing Assays with VarSeq

Golden Helix

There is a strong motivation for labs to bring most, if not all, of their next-gen sequencing pipeline in-house. This is especially relevant for clinical applications where there is a need to validate any routine diagnostics when seeking to provide genetic results to patients. The entirety of the NGS pipeline is highly automatable and comprised of multiple stages but from the geneticist's point of view, the tertiary stage requires the lengthiest review. This stage is where the geneticist sifts through the massive collection of genetic variants to find and report on those most relevant to the patient or population. Unfortunately, the tertiary stage can be a fairly sophisticated process and there aren’t many tools on the market that handle it comprehensively and simply. Many of the tools that are available may have severe limitations on the scale of genomic data they can process or limitations on the types of NGS assays that can be designed. Moreover, their license model may be on an individual sample basis and present cost-benefit hurdles for the user, especially when sample load will inevitably increase. Fortunately, none of these assay or cost-based issues are relevant with Golden Helix products. The goal of this webcast is to expose our viewers to the versatility that GHI VarSeq provides when constructing your dream NGS assay. This demonstration will provide examples of germline and somatic workflows for both single and multi-sample analysis for a variety of different disorders. Please join us and learn more about the analytical possibilities you can achieve when using the VarSeq software.

Prenatal Genetic Screening with VarSeq

Golden Helix

Our past webcast explored the current approaches for screening and diagnosis of genetic disorders in prenatal testing. While the methods available at the time were robust, they were severely limited, creating a need for a higher diagnostic yield and more efficient analysis for a wider range of genetic tests. The solution proposed was to improve and simplify prenatal screening and diagnosis with whole exome sequencing (WES). During that webcast, we highlighted the advantages of WES over traditional methods such as karyotyping and chromosomal microarray, including improved accuracy, granularity, and cost-effectiveness. We also emphasized the potential of WES to expand diagnosis for many other adverse maternal-fetal complications beyond the large aneuploidy events previously covered. However, there was still an intimidation factor when it came to the massive data output from the exome. Fortunately, Golden Helix provided the necessary tools to build and standardize these genetic assays, simplifying the analytical process while leveraging increased diagnostic output. We explored our VarSeq software to demonstrate some example workflows of cases positive for Trisomy 21, an exon loss in DMD related to Duchenne Muscular Dystrophy, and detection of a single base change resulting in a LOF variant in RUNX1 relevant to hereditary leukemia. Our goal was to expose our viewers to the methods of conquering this vast NGS-based data and play a role in dissolving any feeling of intimidation. Overall, exome sequencing has the potential to vastly improve diagnostic outcomes and widen discoveries in the research related to prenatal testing, and Golden Helix products are designed to facilitate this process.

Automated FASTQ to Reports with VarSeq Suite: A fast, flexible solution

Golden Helix

NGS tests in the clinic cover more use cases than ever and are increasingly complex to implement. This leads to an increase in time to validate and bring tests to production, impacting a lab’s ability to be economically viable and serve the needs of patients. Core to the complexity is the expansion of tests to include multiple types of biomarkers and variants, including CNVs, gene fusions, and genomic signatures. The bioinformatics demands of these pipelines require powerful tools with built-in capabilities to handle the diverse needs of modern NGS tests and to integrate and automate the disparate steps leading to clinical insight. Join us in this webinar as we explore the VarSeq suites’ capabilities as a fast, modular, and highly configurable solution for variant analysis and interpretation. We will cover: The bioinformatic diversity of comprehensive genetic tests with NGS Automation of FASTQ to clinical reports without losing control over the results of a test Leverage built-in and custom automation capabilities in the VSClinical cancer guideline workflow to reduce work and improve accuracy Reporting the relevant diagnostic and therapeutic findings for a patient based on the raw genomic data of modern NGS tests requires both human experience and advanced analysis software. We hope you can join us as we unpack how automation is a critical part of implementing NGS tests and furthering the application of precision medicine.

Maximizing the Benefits of Comprehensive Genomic Testing in Cancer Care with ...

Golden Helix

Comprehensive genomic testing via next generation sequencing (NGS) is being increasingly adapted as part of cancer care in conjunction with molecular and immunohistochemical tests. Comprehensive genomic profiling potentially expands the number of targeted therapies that are available to patients, improves patient diagnosis and prognosis, and increases the number of clinical trials that are relevant to patients. However, with these advancements come challenges such as gaps in expertise resulting in inadequate efforts to interpret genomic data accurately and efficiently, poorly coordinated efforts to implement precision care, patients being diagnosed and treated despite inadequate access to relevant information and subsequent lack of patient exposure to all available treatment options. Golden Helix CancerKB v2.0 provides a means of closing the gap, whether you're a beginner who is trying to capture the vast amount of knowledge in the cancer field or an expert who has high sample volume AND needs to keep up with the ever-evolving knowledge of Tier II and III variants. In this webcast, we will discuss and apply Golden Helix CancerKB in the context of cancer precision medicine. Golden Helix CancerKB is systematically curated and reviewed by experts in the field and contains information about cancer genes, biomarkers, and treatments generated from several trusted cancer resources. With VarSeq 2.3.0’s added support for comprehensive cancer genomic profiling tests, Golden Helix CancerKB has expanded to include interpretations for genomic signatures, combination biomarkers, and more investigational (tier II) biomarkers, among several other additions that will be discussed. With the Golden Helix CancerKB database, users will experience a streamlined automatic matching of biomarkers to available drugs and trials which ultimately saves users massive amounts of time and effort while reducing the possibility for errors.

VarSeq 2.3.0: Supporting the Full Spectrum of Genomic Variation

Golden Helix

Next Generation Sequencing allows for the detection of a wide variety of genomic alterations. This includes small mutations, copy number variants and complex rearrangements. However, it can be difficult to annotate, filter, and interpret these alterations. As part of our VarSeq 2.3.0 release, we have greatly simplified this process by allowing you to import, annotate, and filter mutations across all spectrums of genomic variation. This supports concurrent importation of small variants and CNVs as well as complex rearrangements. This release also includes strong support for structural variant annotation, filtering, and interpretation, including structural variant effect prediction. After filtering is complete, any clinically relevant structural variants can be interpreted with the VSClinical AMP Guidelines workflow and included in the final clinical report. Come join us for this webcast to discuss VarSeq’s enhanced import and annotation capabilities, including: Concurrent importation of variants CNVs and complex rearrangements Improved multi-threaded import which dramatically speeds up the importation of large VCFs Annotation of structural variants and prediction of effect Interpretation of structural variants in the VSClinical AMP Guidelines workflow Support for visualization and use of CRAM files as input for computing coverage statistics

Single Sample and Family Based Genome Analysis With VarSeq

Golden Helix

One major hurdle facing medicine is the need to quickly identify and assess the genetic components contributing to rare diseases. It has been estimated that nearly 350 million people suffer from rare diseases, 140 million of which are children, of whom ~30% do not live past their fifth birthday1,2. The specific issue to overcome is reducing morbidity by facilitating rapid diagnosis and treatment. Fortunately, the cost of whole genome sequencing has dropped below the $1000 mark, which not only makes the NGS approach more affordable but has become the status quo method of comprehensive diagnosis for these rare disorders. Currently, there are limited options in the market when it comes to quality software that can scale to this size of data and handle variant processing and evaluation in a timely fashion. Fortunately, Golden Helix has sought to set the market standard for top-quality NGS analysis with our bioinformatic software VarSeq. The focus of this webcast will be to explore example workflows tailored for rare disorders and elaborate on how best to expedite the NGS pipeline process with our command-line tool VSPipeline. During the webcast, we will address the following: Customizing clinically validated NGS workflows with VarSeq for both single sample and trios Demonstrating the automation of ACMG-based guideline review in the VSClinical variant interpretation hub and rendering of customized clinical reports Expediting the NGS workflow via Golden Helix command-line tool VSPipeline We look forward to you joining us for our presentation, where we can demonstrate the value of our products when building your next-gen workflows. Ultimately, we wish to diminish the intimidation of genome workflow design and leave our future customers feeling confident that there is capable software to suit their needs. Bick D, Jones M, Taylor SL, et al. Case for genome sequencing in infants and children with rare, undiagnosed or genetic disease. J Med Genet 2019; 56:783-791. Owen M, Lefebvre S, Hansen C, et al. An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases. Nat Commun 2022; 13: 4057. https://doi.org/10.1038/s41467-022-31446-6

User perspective for somatic variant analysis in VSClinical AMP

Golden Helix

Somatic analysis is a complex and precise process that is constantly evolving. As the volume of available data and the accessibility of sequencing technology increase, so too does the value of a versatile, well-vetted, and efficient workflow solution. In this webcast, we will take a deep dive into the current state of our AMP interpretation software and explore various ways to optimize workflows. For anyone from grizzled VarSeq veterans to those seeing our software for the first time and labs of any size, we will provide a practical overview of our somatic analysis capabilities and how those capabilities scale with improving technology. Throughout this webcast we will be discussing the following: - Universal principles of somatic workflows, providing baseline recommendations - Specific tumor-normal and somatic-only use cases - VSClinical AMP interpretation hub and some variants of interest - Opportunities for automation and how to decrease time to report for increased throughput Join us as we show off the versatility and scalability of our AMP interpretation capabilities!

Maximizing Profitability in your NGS Testing Lab

Golden Helix

The automation of clinical NGS workflows provides a number of important benefits for labs. Automation reduces the time required to produce a clinical report, mitigates the possibility of human error, and improves the precision of clinical results. In turn, these benefits create higher profitability from a P&L perspective. Golden Helix software is designed to meet these needs by automating the full analysis workflow from sequencer to clinical report on a fixed annual subscription model. We are looking forward to discussing the best practices of maximizing profitability in your NGS testing lab and how Golden Helix supports these efforts. Join us in this webinar as we cover how to develop repeatable cancer and germline interpretation workflows that scale from panels to whole exomes and genomes.

Handling a Variety of CNV Caller Inputs with VarSeq

Golden Helix

VarSeq has become renowned for the accuracy of its CNV Caller, and the ease with which VSClinical takes the user through CNV evaluation. Cited in many publications, this well-validated tool brings our customers the ability to run both variant and CNV interpretations in one program, on data ranging from Gene Panels to whole genomes. What is less well known about CNV analysis through VarSeq, is that our users are not only limited to CNVs called through our software. VarSeq CNV is able to import CNVs in several file formats (VCFs, text, or tsv) generated by a wide variety of secondary callers, allowing the user to analyze their externally derived data. In this webcast, we will take you through the basics of CNV analysis with both the VarSeq CNV caller and from several common external CNV callers. Join us in this webinar as we cover: Leveraging the Copy Number Probability and Segregation Algorithm to add power to a CNV Trio workflow. Importing externally called CNVs. Expediting the path to analysis with CNV specific templates. Utilizing the auto-recommendations to efficiently analyze the pathogenicity of several CNV calls and generate clinical reports.

Evaluating Cloud vs On-Premises for NGS Clinical Workflows

Golden Helix

In the era where cloud-based solutions are the default for the modern office, it may not be obvious why many laboratories and testing centers choose to host their data and analysis pipelines on-premises or on self-managed cloud services. Next-generation sequencing enables a precision medicine approach to rare disease diagnostic and cancer therapeutics through its power to detect unique variants in individuals. This data is generated quickly and cheaply but requires a lot of disk space and processing power to arrive at clinically useful insights. When providing a clinical lab service under a regulated environment: data security, long-term affordable storage, and versioning through locked-down pipelines are all factors that must go into the choice of whether to choose a hosted analytics platform versus on-premises solutions or self-managed cloud infrastructure. Join us in this webinar as we cover: The validation and regulatory requirements that inform infrastructure and hosting decisions for NGS labs The cost structure of scaling NGS labs to exomes and genomes Deployment and security architecture for on-premises and self-managed cloud infrastructure Validating and versioning analysis pipelines with clinical tests through self-managed software lifecycles and versioned annotation sources Cybersecurity, patient data privacy, and scalable unit economics play a bigger role than ever before in the planning of NGS lab’s infrastructure choices. We look forward to you joining us as we tackle the trade-offs and choices around these topics and how deployment flexibility is a core feature of the Golden Helix VarSeq Suite.

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VarSeq 2.6.0: Advancing Pharmacogenomics and Genomic Analysis

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ACMG-Based Variant Classification with VSClinical

1. ACMG-Based Variant Classification with VSClinical Eli Sward, Ph.D. Field Application Scientist 20 Most Promising Biotech Technology Providers Top 10 Analytics Solution Providers Hype Cycle for Life sciences

2. Questions & Answers

3. NIH Grant Funding Acknowledgments • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: • Award Number R43GM128485-01 • Award Number R43GM128485-02 • Award Number 2R44 GM125432-01 • Award Number 2R44 GM125432-02 • Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 • PI is Dr. Andreas Scherer, CEO Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

4. Who Are We? Golden Helix is a global bioinformatics company founded in 1998 Filtering and Annotation ACMG Guidelines Clinical Reports CNV Analysis Pipeline: Run Workflows Variant Warehouse Centralized Annotations Hosted Reports Sharing and Integration CNV Analysis GWAS | Genomic Prediction Large-N Population Studies RNA-Seq Large-N CNV-Analysis

5. Cited in 1,000s of Peer-Reviewed Publications

6. Over 400 Customers Globally

7. SIMPLE, SUBSCRIPTION- BASED BUSINESSMODEL o Yearlyfee o Unlimitedtraining&support SOFTWARE ISVETTED o 20,000+ usersat 400+ organizations o Quality&feedback DEEPLY ENGRAINED IN SCIENTIFIC COMMUNITY o Give backto thecommunity o Contributecontentandsupport INNOVATIVESOFTWARE SOLUTIONS o Cited in1,000s ofpublications When you choose Golden Helix, you receive more than just the software

9. VarSeq Suite Simple Flexible Scalable Variantannotation filtering, andinterpretation PowerfulGUIwith richvisualizations Repeatable workflows

10. VarSeq - Annotations • Curated Public Databases o 1kG Phase3 Variant Frequencies o RefSeq Genes, NCBI o ClinGen Dosage Sensitivity Mapping o dbNSFP Functional Predictions • Lock down version • Notifications for track updates • Premium Annotations: o CADD o COSMIC o Conservation Scores o SIFT/PolyPhen2 o Splice Site Algorithms o OMIM phenotypes and Genes o dbSNP o ExAC o ClinVar o CIViC

11. VSClinical - Value • Consistent results • Shorten learning curve • Staying abreast of new developments

12. VSClinical - ACMG Rules for Classification Richards et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 2015, Genet Med 17: 405-424. Pathogenic Likely Pathogenic Uncertain Significance Likely Benign Benign Rules Presented in VSClinical

13. VSClinical – Four-Phased Workflow 1. Filter and select variants for evaluation • Follows existing VarSeq filter workflow 2. Assess all evidence for variant • Presented in VSClinical interpretation hub 3. Develop final classification • Directly follows ACMG Guidelines ‐ 33 criteria for evaluating evidence ‐ 5 possible classifications built from criteria ‐ Include caveats and discussion for evaluating criteria in different contexts • Develop and catalog variant interpretation 4. Include interpretation in final clinical report Benign Pathogenic Uncertain Significance

14. VSClinical – Clinical Report • Prepared “Templates” • ACMG Standard Germline Report • Configurable Global Settings ‐ Logo ‐ Lab information ‐ Test description/disclaimers • Customizable Sample Inputs • Patient Information • Test Results • Selected Variants Added • Per-Variant Information • Customizable • Default values are scriptable • Rendering is entirely programmatic

15. ProjectDemonstration

16. Questions & Answers

17. Find Golden Helix in Booth #622!

18. NIH Grant Funding Acknowledgments • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: • Award Number R43GM128485-01 • Award Number R43GM128485-02 • Award Number 2R44 GM125432-01 • Award Number 2R44 GM125432-02 • Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 • PI is Dr. Andreas Scherer, CEO Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

19. Questions & Answers

Editor's Notes

GoldenHelix is a global bioinformatics software and analytics company that enables research and clinical practices to analyze large genomic datasets. We were originally founded in 1998 based of pharmacogenomics work performed at GalxoSmithKline who was and still is a primary investor in our company. We currently have two flagship products Varseq and SNP and Variation Suite (SVS) for short. SVS is our research application platform that enables researchers to perform complex analysis and visualizations on genomic and phenotypic data. SVS has a broad range of tools to easily perform GWAS, Genomic Prediction, Differential expression analysis on RNA-Seq Data and has the ability to process CNV analysis, which we will demonstrate today. VarSeq, on the other hand, is our clinical application platform that is used for filtering and annotating variants of interest. We can also evaluate variants according to the ACMG guidelines with VSCLincal and have the option to automatically create clinical reports from the results of various workflows. Using the same software, we can also perform CNV analysis on targeted gene panels and whole genome sequencing, which we will demonstrate today and We also have an add-in function called VSPipeline – which can take the workflow that you created and automates the process with very little human interaction. Now all of the information produced from VarSeq can be stored in our Warehouse solution, which is designed to be installed on a server location and serve as a repository for your variants evaluations, annotations, and hosted reports. Lastly, VSWarehouse can also be implemented for sharing and integration between license holders.
Our software has been very well received by the industry. We have been cited in thousands of peer-reviewed publications and that’s a testament to our customer base.
We work with over 400 organizations all over the globe. pharmaceutical companies, Bayer and Lilly top-tier institutions, Stanford and yale government organizations, NCI clinics, Sick kids genetic testing labs, prevention genetics and lineage With now well over 20,000 installs of our products and with 1,000’s of unique users. So why is this relevant to you?
This means that over the course of 20 years our products have received a lot user feedback, which we are always very receptive to when developing and releasing newer versions of our products. This user feedback allows our software to stay relevant and well vetted in it’s capabilities and qualities which builds our products reputation, trust, and client experience. We also stay on the forefront of the needs of the industry and community by regularly attending conferences and providing useful product information via eBooks, tutorials, and blog posts. Your access to the software is a simple subscription based model where we don’t charge per sample nor per version. You also maintain full access to our support and training staff to get you up to speed quickly with your analysis
Golden Helix provides the workflow that allows starting with an initial FASTQ file all the way down to a clinical report. Sentieon can perform the alignment and variant calling creating the VCF and BAM files which can then be implemented in VarSeq for variant annotation, filtering and interpretation AND CAN be used to create a clinical report. Warehouse allows the storage for this information which provides researchers and clinicians with access to this information to view previous findings.
VarSeq is a power, flexible, and scalable variant annotation filtering and interpretation engine. This commercial grade software designed for your local hardware so it is a desktop application that is installed locally on your computer and is very simple to use (as well see). VarSeq also has GenomeBrowse built in which allows rich visualization of for a variety of data types built right into the software. In addition with Varseq we have the ability to build and run repeatable workflows within the GUI and on the command line with our VSpipeline add-on tool. So once you have developed a workflow in VarSeq, and decided the type of filtering you would like to do, what annotation sources you would like, you can save that workflow as a template which can really streamline the analysis time.
VaqSeq is a filtering and annotation engine so of course that means we are only as good as the annotations that we have available. Varseq is backed by an extensive list of publically curated data sources – this is where you are going to see the common variant frequency catalogs from 1k genomes, ExAC, NHLBI the exome variant server data. These are all free for use for anybody within the software. If there is a public source of data that we don’t currently support that you would like added to the software, all you have to do is let us know and we can look into getting that supported. With annotation sources and workflows in VarSeq, Any template created is going use a specific version of these annotations sources and lock it down and this is not something that we overwrite automatically. For example, you create a workflow and annotate your variants of interest using ClinVar annotation source. ClinVar releases updated information on a monthly schedule and we do try to stick to that monthly schedule. So once a month there is a new version of ClinVar that becomes available. if your workflow is specifying that you were using a (Octobers), then anytime you run that workflow, the (Octobers) version of ClinVar will be used. But we will provide a notification within the software that tells you when a new version of ClinVAR becomes available. So with just a few clicks, you can updating your workflow with a newer version of ClinVar. We are not going to do it for you because we are cognizant of anybody that needs to validate those sources and so your workflows don’t get overwritten. We also have a couple of annotation sources that we consider secure or cloud based annotations because these are not freely available for public use. There is a fee associated with these annotation sources to get access to them, but your sales representative can talk more about these when he talks licensing and getting everyone set up. So these sources are 1.) MedGenome OncoMD which is specific cancer database which provides drug targeting information as well as supporting clinical trial information specifically involving cancer mutations. 2.) OMIM information is available on the cloud source. We have their genes, phenotypes, and variants information. This information is a part of our reporting functionality and is used to fill in a lot of information regarding particular variants. We will explore this when we discuss reporting in VarSeq. 3.) CADD functional prediction scoring tools as well. If you have your own custom annotation source that you would like made available in the software, we have tools available that can basically take any delimited text file, a VCF file, or BED file just a wide variety of other sources that can be taken into the software using our convert wizard and converted into a source that can be used as an annotation source or filtering option within the software.
The value of VS Clinical is that it provides a simple solution to a complex variant classification process. VSClinical reduces user oversight and fatigue by automating the ACMG Guidelines. This automation, in turn, ensures that classifications and interpretations are consistently created and can reduce analysis time when analyzing large numbers of samples. Because VSClinical is also intuitive, there is a short learning curve with familiarization. This can enhance workflow efficiency by giving even the newest user the capability of thoroughly classifying more variants in less time. And lastly, automating the ACMG guidelines will allow users of VSClinical to have more time to stay abreast new developments including interpreting and processing variants and it will alleviate the complexity of setting up taxing bioinformatic pipelines. That said, lets now focus on how VSClinical directly follows the ACMG rules for classifying variants.
VSClinical directly utilizes the rules sourced from the ACMG standard guidelines article, and shown are the 5 potential classifications and the associated rule logic for all relevant criteria. Focusing on the pathogenic classification, you can see a number of different paths the criteria can follow. For example, in option 1, pathogenicity can be achieved with a single “very strong” PVS1 criteria in addition to four other options (a,b,c,d). Now even the most adept clinicians familiar to the guidelines suffer from this tedious manual process, let alone the complexity in teaching these fundamentals to new technicians. But as mentioned, VSClinical is an automated solution to the complex ACMG guidelines process, so in this demonstration we will present how VSClinical follows the true to form ACMG classification rules. As an example, VSClinical outputs the final classification and the rule logic which we can see for a final Pathogenic classification for a RAF1 variant that was determined based on rule 3, which is one strong, three moderate, and two supporting criteria. Ultimately, even with the automation of VSClinical the user will always be presented with the true to form ACMG classification rules. That said, now lets focus on some other key concepts of VSClincal.
With any variant workflow, the first goal is to annotate and filter your variants to a subset that are clinically interesting. Because the ACMG classifier is also an annotation source it can be easily added to your predefined workflow. Next, you want a simple approach to investigate all the available evidence for any specific variant. This evidence is directly fed into the ACMG classifier to produce an autoclassification, but also all of the annotation evidence can be investigated in the VSClinical interpretation interface. After processing all available annotation evidence for the variant, the user will be presented with the scored ACMG criteria that then follows the ACMG rules for the 5 potential final classifications. VSClinical also provides accountability for possible caveats and links to discussions important for less clear variants. Once the evaluation is complete, the variant and the classification interpretation are stored in the user’s catalog for future reference. The final stage of this process is to render an ACMG based clinical report. VarSeq has a custom reporting capability that automatically grabs any classified variants with their cataloged interpretation and this reporting capability is performed all in one suite.
With Varseq users can create custom ACMG guideline based clinical report just like the one seen here. With some easy configurable options users can customize their report to include their lab logo, patient information and test description and disclaimers. You can also select which variants you want to pull into the clinical report. More detailed customizations are also optional with some javascript and html experience that allows for the inclusion of any additional annotation or samples fields in your VarSeq project.
GoldenHelix is a global bioinformatics software and analytics company that enables research and clinical practices to analyze large genomic datasets. We were originally founded in 1998 based of pharmacogenomics work performed at GalxoSmithKline who was and still is a primary investor in our company. We currently have two flagship products Varseq and SNP and Variation Suite (SVS) for short. SVS is our research application platform that enables researchers to perform complex analysis and visualizations on genomic and phenotypic data. SVS has a broad range of tools to easily perform GWAS, Genomic Prediction, Differential expression analysis on RNA-Seq Data and has the ability to process CNV analysis, which we will demonstrate today. VarSeq, on the other hand, is our clinical application platform that is used for filtering and annotating variants of interest. We can also evaluate variants according to the ACMG guidelines with VSCLincal and have the option to automatically create clinical reports from the results of various workflows. Using the same software, we can also perform CNV analysis on targeted gene panels and whole genome sequencing, which we will demonstrate today and We also have an add-in function called VSPipeline – which can take the workflow that you created and automates the process with very little human interaction. Now all of the information produced from VarSeq can be stored in our Warehouse solution, which is designed to be installed on a server location and serve as a repository for your variants evaluations, annotations, and hosted reports. Lastly, VSWarehouse can also be implemented for sharing and integration between license holders.

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Editor's Notes