Actionable Genes, Core Databases, and Locus‐Specific Databases

Amélie Pinard, Morgane Miltgen, Arnaud Blanchard, Hélène Mathieu, Jean‐Pierre Desvignes, David Salgado, Aurélie Fabre, Pauline Arnaud, Laura Barré, Martin Krahn, Philippe Grandval, Sylviane Olschwang, Stéphane Zaffran, Catherine Boileau, Christophe Béroud, Gwenaëlle Collod‐Béroud

Adoption of next generation sequencing (NGS) in a diagnostic context raises numerous questions with regard to identification and reports of secondary variants (SVs) in actionable genes. To better understand the whys and wherefores of these questioning, it is necessary to understand how they are selected during the filtering process and how their proportion can be estimated. It is likely that SVs are under-estimated and that our capacity to label all true SVs can be improved. In this context, Locus Specific databases can be key by providing a wealth of information and enabling classifying variants. We illustrate this issue by analyzing 318 SVs in 23 actionable genes involved in cancer susceptibility syndromes identified through sequencing of 572 participants selected for a range of atherosclerosis phenotypes. Among these 318 SVs, only 43.4% are reported in HGMD Professional vs. 71.4% in LSDB. In addition, 23.9% of HGMD Professional variants are reported as pathogenic vs. 4.8% for LSDB. These data underline the benefits of LSDBs to annotate SVs and minimize over interpretation of mutations thanks to their efficient curation process and collection of unpublished data. This article is protected by copyright. All rights reserved.