Next-generation sequencing (NGS) technology with deep sequencing coverage enhances sensitivity to detection and allows identification allele balances suggestive of low-level mosaicism that was recently undetectable by Sanger sequencing. Detection of a mosaic variant in a patient being tested for an inherited cancer predisposition poses challenging considerations for clinical interpretation and genetic counseling.
To facilitate understanding of the clinical manifestations, this presentation describes the causative biologic events underlying germline, somatic, and gonosomal constitutional mosaicism. Because a finding of mosaicism in the peripheral blood may have prognostic significance related to risk for development of a hematopoietic malignancy, the presentation explores the concept and criteria for the newly proposed entity of “clonal hematopoiesis of indeterminate significance” and discusses the role of TP53 mutations in the origin and evolution of selected clones with increased neoplastic potential created secondary to cytotoxic chemotherapy and/or radiotherapy exposure.
Follow-up clinical management recommendations are presented that can be used when a mosaic variant is unexpectedly found in the peripheral blood. Finally, because mosaic findings are expected and can affect inherited genetic disease testing in patients with known hematopoietic malignancies, the presentation also covers important considerations for clinical interpretation, including limitations to testing in patients testing with known circulating hematopoietic neoplasms.
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.
Several genes have been implicated in causing genetic forms of epilepsy. In this webinar, Dr. John Millichap will describe the molecular impact of KCNQ2, a gene responsible for causing early onset epilepsy. He will also share insight into the advocacy work of two organizations that provide education, resources, and support to affected families.
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.
Invitae is making high-quality cardiovascular genetic testing faster and more affordable than ever before. Our expanded test menu includes broad, comprehensive, and combined panels, as well as single-gene tests.
In this webinar, Invitae genetic counselor Nicole M. Johnson describes our new cardiovascular offerings as well as our flexible menu, with which you can easily select a pre-curated panel, combine multiple panels, or customize your own panel with one click. Our affordable and transparent pricing allows you to choose the right genes for your patient, knowing exactly what it will cost.
Invitae’s team of medical and genetic experts combines full-gene next-generation sequencing and exonic copy number analysis with rigorous evidence-based variant classification methods to provide clearly interpreted diagnostic results.
Sequencing the PMS2 gene is difficult. Accurately analyzing complex portions of this gene for sequence and del/dup variants usually requires expensive and complex lab techniques. We have developed a method for full PMS2 sequencing and deletion/duplication analysis that offers both the same high quality and the same affordable price you’ve come to expect from Invitae.
Our new, highly accurate method covers both PMS2 and its pseudogene, PMS2CL. The trick lies in evaluating all reads from both genes as if they belonged only to PMS2, and then using a bioinformatic screen to call variants across this region. In cases where no variants are found, the sample can continue through the testing process. In cases with positive screen findings, we use alternate technologies to determine whether the variant is in PMS2 or PMS2CL.
Join our webinar to learn about Invitae’s innovative approach to PMS2 exons 12-15, including how we thoroughly validated this process.
Charcot-Marie-Tooth disease (CMT) is a group of hereditary neuropathies that is characterized by weakness of the foot and lower leg muscles. Symptoms are caused by an impairment in the ability of peripheral nerves to conduct signals throughout the body and result in reduced motor control and sensation in the arms and legs. Different subtypes of CMT exist and genetic testing is often needed to identify the specific subtype. In this webinar, licensed genetic counselor Carly Siskind will explore the underlying genetics, diagnostic options, and clinical management strategies for CMT. She will also discuss the CMT Association and its role as a support resource for clinicians and for patients who are managing this progressive condition.
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.