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.
Hypertrophic cardiomyopathy (HCM) is one of the most common single-gene inherited cardiovascular conditions and the most common cause of sudden cardiac death in athletes in the United States. It can present anytime from infancy through adulthood.
Defined by unexplained, abnormal thickening of the heart muscle, or myocardium, HCM can impair both how the heart contracts and the heart’s electrical system, leading to palpitations, dizziness, fainting, chest pain, shortness of breath, and, in some cases, sudden cardiac arrest or death.
Individuals with clinical symptoms of HCM may benefit from diagnostic genetic testing to better understand risks, confirm a diagnosis, and inform management. Asymptomatic individuals within a family with a known HCM mutation may also benefit, as testing may clarify their personal risk of developing HCM and allow for the consideration of medical management.
In this webinar, internationally renowned cardiologist and scientist Dr. Christopher Semsarian offers an overview of the diagnosis and management of HCM from a molecular, genetic, and clinical perspective, and discusses published HCM guidelines.
Noonan syndrome is a genetic condition, often identified at birth, that can be characterized by a wide spectrum of symptoms and physical features. Clinical findings of Noonan syndrome (and related disorders) include congenital heart defects, craniofacial features, cutaneous abnormalities, tumor development, and more. Noonan spectrum disorders are known as RASopathies due to their impact on the RAS-mitogen-activated protein kinase (MAPK) intracellular signaling pathway. Invitae offers panel testing for conditions that fall under this spectrum.
In this webinar, Britt Johnson will describe both the underlying genetics, as well as the laboratory offerings relevant to obtaining a diagnosis for patients presenting with these clinical features.
As many as 5 to 15% of gynecological cancers are inherited. In this webinar, Invitae’s genetic counselor, Tali Ekstein, will review Invitae’s Hereditary Gynecologic Cancers Panel. We will discuss when this panel may be considered, review the key genes, and cover case studies related to ovarian and endometrial cancers. We will also review how the information obtained from genetic testing may benefit your patient and their family members.
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.
Hereditary cancer syndrome testing is becoming increasingly prevalent, yet adoption by community oncology practices has been minimal. Raluca Kurz, a genetic counselor at Invitae, will discuss current drawbacks to incorporating genetic testing into a community oncology practice and how Invitae is helping to overcome these barriers.
Examples include report interpretation, turnaround time, and genetic counseling. We’ll discuss BRCA and the high-risk breast cancer genes as well as management guidelines. The webinar will close with a few case studies of reviewing a family history and then choosing the correct test for your patient.
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.
The use of multi-gene panels in hereditary cancer clinics is increasing. Heather Hampel, MS, CGC and Tuya Pal, MD will present cases from their clinical experience that have utilized panel testing. The speakers will highlight the potential benefits of panels as well as difficulties including managing patient expectations, dealing with positive results in moderate penetrance genes and multiple VUSes per patient.
New research findings from Stanford published in JCO on multi-gene panels for hereditary cancers: what have we learned about improving patient care?
According to a new publication from Stanford in the Journal of Clinical Oncology, as many as 10 percent of women with a personal or family history of breast or ovarian cancer have at least one genetic mutation that, if known, would prompt their doctors to recommend changes in their care, according to a new study by researchers at the Stanford University School of Medicine.
The women in the study did not have mutations in BRCA1 or BRCA2 (mutations in these genes are strongly associated with hereditary breast and ovarian cancer), but they did have mutations in other cancer-associated genes.
The study was conducted using what’s known as a multiple-gene panel to quickly and cheaply sequence just a few possible genetic culprits selected by researchers based on what is known about a disease. Although such panels are becoming widely clinically available, it’s not been clear whether their use can help patients or affect medical recommendations.
This seminar aims to answer those questions, both from the research study, featuring lead author Dr. Allison Kurian.