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.