Germline/Hereditary NGS Analysis in GO Pathology Workbench
As the genomic cost curve bends toward ever smaller sums, the world has been inundated with genomic data. This has brought the issues of analysis and interpretation to the fore (What does this single change to a sequence of three billion bases of DNA do?). Medical genetics has made great strides with certain genes and phenotypes, but there is still considerable uncertainty. Progress on this front has been more plodding, stymied by the expense of careful biocuration and deep phenotyping, the rarity of high-impact variation, and the overall complexity of human biology. We can continue to construct mountainous piles of genomic data, but this accrual process does not by itself resolve the stubborn complexity of variant interpretation.
In addition to the scientific challenges of medical genetics, everyday practice has many of its own. Most of these revolve around the most important stakeholder, patients. Patients can be strung along on seemingly interminable diagnostic odysseys or confused by ambiguous or sophisticated test results. The entire patient-facing side of the equation is fraught with unknowns. Not only is it often difficult to communicate effectively about results, but it can be devastating to have to report incidental findings that upend a patient’s (and their family’s) life. Patients are anxiously awaiting diagnostic clarity and precision care, and professionals in clinical genetics deserve state-of-the-art support when providing for patients. The complexities inherent to diagnosing hereditary disease or disease risk require rigorous and reliable solutions that streamline reporting and optimize for clarity.
As part of an effort to provide a standardized and rigorous approach to variant interpretation and classification, the American College of Medical Genetics (ACMG) and the Association for Molecular Pathology (AMP) published a joint consensus recommendation for the classification of germline sequence variants in 2015. The ACMG/AMP guideline provides a qualitative framework that enables reliable analysis of variant pathogenicity by drawing from several sources: population databases (e.g. gnomAD, ExAC, 1000 Genomes, and All of Us), computational and predictive tools (e.g. CADD, REVEL, PolyPhen2, etc), experimental studies, allelic contexts, segregation data, and clinical findings. The ACMG/AMP framework has been built on and further specified by related groups of geneticists. This includes work by experts from the Clinical Genome (ClinGen) Resource, who maintain a detailed and rigorous SOP for the entirety of variant curation. ClinGen’s published variant curations are eligible for FDA Recognition, which makes them a useful resource for streamlining reporting. The venture of variant interpretation and classification is open-ended, always ongoing. It is responsive to new research findings and other changes in practice. In this vein, ACMG/AMP is expected to update to a semi-quantitative framework for their upcoming fourth version. This underscores the dynamic and collaborative nature of variant analysis. The best solutions for supporting germline analysis will be versatile and catalyze collaboration (i.e. facilitating the publication of variant curations on ClinVar).
GenomOncology (GO) has more than twelve years of experience and expertise in precision medicine care. Recently, we released an upgraded version of GO Pathology Workbench, our software platform for tertiary analysis and reporting of next generation sequencing (NGS) and other molecular testing results. This version includes expanded support for germline testing, reinforcing its capacity to conduct tertiary analysis across all assays, ranging from tumor sequencing, hereditary cancer, rare diseases, and all somatic and germline panels through whole genome analysis.
Regarding our germline enhancements, the GO Pathology Workbench (GO PWB) can ingest germline VCF files derived from any secondary analysis platform, quickly annotate variants with a slew of resources, and provide streamlined support for variant interpretation and reporting on findings.
Annotation is a common feature of many germline analysis applications, but the GO PWB also has a built-in, customizable auto-classification algorithm, the Variant Interpretation Endpoint (VIE). VIE can be used to detect existing classifications, whether from ClinGen’s FDA-recognized dataset, or a custom classification database that can be easily integrated into the user’s private instance of GO PWB. For variants without existing classifications, users may use GO PWB’s ACMG/AMP classification worksheet to complete a rigorous but streamlined curation. A user can easily apply codes and strengths to variants, adding detailed notes and evidence as they work. When the worksheet is complete, GO PWB will use the assigned codes to calculate the variant classification according to the ACMG/AMP framework. In other words, a reportable classification that designates a variant’s pathogenicity will be provided and stored. If the same variant is ever identified again, GO PWB will automatically populate with the prior relevant curation and final classification. The user will always have the opportunity to re-evaluate the variant if new information becomes available. Once all variants have been evaluated, GO PWB will generate a report which can be fully customized to the client’s specifications.
The value of GenomOncology’s platform will be immediately recognizable to users. First, it is a single platform and database for all somatic and germline testing. This creates a coherent user experience and product ecosystem. Current clients can integrate GO PWB with other GO applications without friction, and new clients can readily expand on solutions as needed. Second, GO’s platform has universal compatibility, able to work from any assay, instrument, biomarker type, and file format. Third, GO not only quickly and thoroughly annotates variants, but also stores all user-generated curations in a central database where they can be easily accessed and updated. Fourth, GO enables fully customizable reporting, providing users both off-the-shelf templates and modifiable ones. With this and more, GenomOncology is a go-to platform for somatic and germline analysis.