Publication: Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance
Authors
Castillo-Guardiola, Verónica ; Rosado-Jiménez, Laura ; Marín-Vera, Miguel ; Macías-Cerrolaza, José Antonio ; García-Hernández, Rosario ; Zafra-Poves, Marta ; Sánchez-Henarejos, Pilar ; Moreno-Locubiche, María Ángeles ; Cuevas-Tortosa, Encarnación ; Arnaldos-Carrillo, María ; Ayala de la Peña, Francisco ; Alonso-Romero, José Luis ; Noguera Velasco, José Antonio ; Ruiz Espejo, Francisco ; Sarabia Meseguer, María Desamparados
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Publisher
Elsevier
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DOI
https://doi.org/10.1016/j.ejmg.2022.104468
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info:eu-repo/semantics/article
Description
© 2022 Elsevier Masson SAS. All rights reserved. This document is the Published version of a Published Work that appeared in final form in European Journal of Medical Genetics. To access the final edited and published work see https://doi.org/10.1016/j.ejmg.2022.104468
Abstract
Introduction: BRCA1 and BRCA2 are the two main genes causing hereditary breast and ovarian cancer (HBOC). However, thanks to the development of Next Generation Sequencing (NGS), other genes linked to this syndrome (CHEK2, BRIP1, ATM and PALB2 among others) can be analysed. Material and methods: an analysis by multigene panel testing was performed in 138 index cases (ICs) from HBOC Spanish families with a previous non-informative result for BRCA1/2. The BRCA Hereditary Cancer Master™ Plus kit, including 26 actionable and candidate genes related to HBOC was employed. Once classified, an algorithm was employed to prioritized those variants of unknown significance with a higher risk of having a deleterious effect. Moreover, a mRNA splicing assay was performed for the prioritized VUS c.3402+3A > C in ATM, located at intron 23. Results: A total of 82 variants were found: 70 VUS and 12 pathogenic or probably pathogenic variants. The diagnostic yield in actionable genes non-BRCA was 7.97% of the total tested ICs. Overall, 19 VUS were prioritized, which meant 27% of the 70 total VUS. RNA analysis of the variant 3402+3A > C confirmed a deleterious impact on splicing. Discussion: The implementation of a multigene panel in HBOC studied families improved the diagnostic yield, concordant with results obtained in previous publications. Due to the important number of VUS obtained in NGS, the application of a prioritization algorithm is needed in order to select those variants in which it is necessary to conduct further studies.
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Citation
European Journal of Medical Genetics 65 (2022) 104468
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