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.
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.
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.