Next-generation sequencing (NGS) effectively detects both del/dup events and sequence alterations, and has a number of advantages over traditional techniques. Intended for genetic counselors, physicians, and other healthcare providers, this presentation will help you to:
Dr. Vatta is a clinical molecular geneticist with more than 20 years of experience in cardiovascular genetic research and 10 years in cardiovascular genetic diagnostics. Before joining Invitae, Dr. Vatta was the Director of the Cardiovascular Genetics Section at the Indiana University Molecular Genetics Diagnostic Laboratory in the Division of Diagnostic Genomics and Associate Professor of Clinical Medical and Molecular Genetics at Indiana University. There, he led the development and launch of next-generation sequencing analysis for clinical testing. Dr. Vatta received his Ph.D. in molecular genetics from the Scuola Internazionale Superiore di Studi Avanzati/International School of Advanced Studies (SISSA/ISAS) in Trieste, Italy, with a thesis on the “Molecular Genetic Approach to the Study of Dilated Cardiomyopathy."
Lynch syndrome is characterized by familial predisposition to cancers of the colon, endometrium, ovary, stomach, and urinary tract. 4–11% of cases are caused by variants in PMS2. Testing for inherited PMS2 variants is hampered by a pseudogene, PMS2CL, which has nearly identical homology to PMS2 in exons 12–15 of the gene. Therefore, it is difficult to determine if a variant is in PMS2 or PMSCL and different and innovative methods are needed for analysis of this region.
Erin O’Leary, MS, LCGC discusses Invitae’s methods to disambiguate variants detected in PMS2 exons 12–15. Variant interpretation in this region of PMS2 is highly dependent on laboratory methods. Therefore, a laboratory’s technology and methods are crucial in avoiding misdiagnoses of Lynch syndrome and inappropriate management.
What does it mean to be a gold standard in genetic testing? At Invitae, we believe there’s a new gold standard today, one that includes both high quality testing and a dedication to improving medicine through data sharing.
In this webinar, Steve Lincoln, head of scientific affairs at Invitae, discusses ways in which you can make sure the testing you provide your patients meets a high standard of excellence.
Invitae’s philosophy is to combine thoroughly validated analysis with a dedication to submitting our variant interpretations into the public domain. In this way we are setting a new gold standard.
Invitae recently announced the launch of hundreds of new genes and expanded panels. What does that mean for hereditary cancer testing? In this short webinar, Invitae genetic counselor Tali Ekstein describes the new and expanded panels, explains the reasoning behind each grouping of genes, walks through how to order the new panels and genes, and shares the resources we have developed for you.
For additional information on limited-evidence genes for hereditary cancer, please see the webinar Hereditary Cancer Limited-Evidence Genes: What are They?
With the recent launch of new panels and genes, Invitae has introduced a new category of genes: limited-evidence genes. Invitae has rigorously evaluated the literature to determine whether an association between the gene and specific condition has been established. In this webinar, we will review cases explaining the groupings of specific panels and the evidence.
Testing panels of hereditary cancer genes represents an important advance in medicine; however, the clinical impact of these tests is not yet fully understood. In this webinar, we will discuss a recent study on the clinical utility of panel testing in hereditary breast and ovarian cancer patients, presented at the American Society of Clinical Oncology meeting on June 1, 2015.
More than 1,000 BRCA1/BRCA2-negative individuals who met appropriate criteria for BRCA testing were studied. Of the 63 who carried non-BRCA mutations, the patient management implications of these findings were assessed under uniform criteria based on current practice guidelines. The study found that the majority of non-BRCA positive results would warrant consideration of a change in care for the patient, over and above any actions that would be considered based on personal and family history alone. Moreover, the study showed that genetic testing of family members would also be warranted given the management implications for relatives who tested positive for these non-BRCA genes.
These results show that panel testing can yield clinically relevant and actionable findings with potentially beneficial management impact for substantially more patients than BRCA1/BRCA2 testing alone can.
The study was conducted as a collaboration between Invitae, Massachusetts General Hospital, the Stanford Cancer Institute, and Beth Israel Deaconess Medical Center.
With increasing use of high-throughput sequencing and multi-gene panels for diagnostic purposes, there is growing concern about the potential for inconsistent variant classifications among clinical labs. The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) recently drafted new standards and guidelines for the interpretation of sequence variants (ISV) to address this concern. Draft versions of these guidelines were shared broadly with the clinical genetics community, feedback was incorporated, and an evidence-based checklist for interpreting Mendelian disease variants has now been published (Richards et al., Genet Med 2015). This checklist represents a major step toward evidence-assessment standardization and variant-classification consistency. However, many ISV criteria are quite expansive, which could result in inconsistency in their application. To date, a rigorous study has not been published examining the impact of these new guidelines on variant classification and clinical reporting. It also remains to be seen whether the new evidence checklist results in increased interpretation concordance between clinical laboratories. We considered these issues when validating our own laboratory’s classification procedures, which are based on the new ISV guidelines.
With the 2015 ACMG ISV guidelines as our guide, we developed Sherloc, a score-based classification system with detailed evidence criteria, inherent logic for handling interdependent evidence, and comprehensive notes outlining caveats, various use cases, and evidence considerations for each criteria. This system has been implemented in our clinical-testing workflow and refined over the past 20 months. To evaluate the concordance of Sherloc classifications with current community standards, we compared classifications of over 800 variants to a consensus classification derived from ClinVar submissions. Importantly, we find Sherloc interpretations to be highly consistent with those submitted to ClinVar.
Joubert syndrome is a genetic condition that is characterized by congenital malformations of the brain stem and an absence or underdevelopment of the cerebellar vermis (cerebellar vermis hypoplasia). This disorder usually manifests in early childhood and includes a spectrum of neurological symptoms, including hypotonia, developmental delay, breathing abnormalities (e.g., episodic tachypnea-apnea), atypical eye movements (e.g., oculomotor apraxia), and progressive truncal ataxia. Joubert syndrome presents with different disease severities and different symptoms, including retinal disease, renal disease, oculorenal disease, hepatic disease and oro-facial-digital features. From a genetic perspective, it is a complex disorder.
In this webinar, genetic counselor Dana Knutzen will present the fundamentals of Joubert syndrome genetics while also describing her own professional experiences with this condition, particularly in the context of her advocacy work with the Joubert Syndrome & Related Disorders Foundation.
A rigorous, reproducible and transparent variant classification system is a cornerstone of the practice of clinical molecular genetics. In this seminar, we will discuss the kinds of evidence considered in an interpretation, caveats associated with those evidence types, and the methods Invitae employs to synthesize multiple lines of evidence into a final interpretation. We will also discuss our experiences implementing and augmenting the upcoming revisions to the ACMG/AMP/CAP classification guidelines (2014 draft).
Defining the Questions
Scott Topper, PhD, FACMG, will discuss the intellectual framework that guides the approach to variant interpretation, the questions asked during the variant classification process, the types of evidence reviewed, and possible pitfalls associated with different evidence types.
Behind the Scenes
Keith Nykamp, PhD, will introduce the evidence structure behind Invitae’s variant classification system and illustrate the application of this system with case studies. He will also demonstrate how the evidence and logic behind a variant classification is presented in the clinical report.
Compared to traditional approaches, next-generation sequencing (NGS) can simultaneously reduce the cost and increase the breadth of DNA assays, thus helping to make clinical genetic testing more accessible and more comprehensive. NGS was first introduced in 2005, and while it initially had limited performance and uses, continuous innovation has delivered robust NGS platforms that are widely accepted for clinical use.
NGS is most often used to detect relatively small DNA sequence alterations; however, NGS-based methods to detect larger deletions and duplications (del/dup events) were first published in 2009. Like NGS generally, these methods have evolved rapidly, and the most recent versions allow appropriately equipped laboratories to deliver high-quality results for both small and large DNA alterations from a single NGS assay.
In this seminar, we will briefly review approaches used for del/dup calling using NGS. We will focus on clinical data from our laboratory, which shows high concordance between our NGS-based approach and traditional del/dup test results. We also will illustrate cases in which the combination of NGS-based sequence and del/dup analysis resolves complex events that can be challenging for traditional approaches.