RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant

Abstract Case–control studies have shown an association of BARD1 with hereditary breast and/or ovarian cancer (HBOC) predisposition. BARD1 alternatively spliced isoforms are abundant and some are highly expressed in different cancer types. In addition, a number of BARD1 germline pathogenic variants...

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Autores principales:	Paula Rofes, Marta Pineda, Lídia Feliubadaló, Mireia Menéndez, Rafael de Cid, Carolina Gómez, Eva Montes, Gabriel Capellá, Joan Brunet, Jesús del Valle, Conxi Lázaro
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e832dc5f39ae4707b42c6464ddf64fb7
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spelling	oai:doaj.org-article:e832dc5f39ae4707b42c6464ddf64fb72021-11-28T12:19:35ZRNA assay identifies a previous misclassification of BARD1 c.1977A>G variant10.1038/s41598-021-02465-y2045-2322https://doaj.org/article/e832dc5f39ae4707b42c6464ddf64fb72021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02465-yhttps://doaj.org/toc/2045-2322Abstract Case–control studies have shown an association of BARD1 with hereditary breast and/or ovarian cancer (HBOC) predisposition. BARD1 alternatively spliced isoforms are abundant and some are highly expressed in different cancer types. In addition, a number of BARD1 germline pathogenic variants have been reported among HBOC patients. In previous reports, BARD1 c.1977A>G variant has been classified as pathogenic since it produces a frameshift transcript lacking exons 2 to 9. In the present study, we sought to validate the mRNA splicing results previously published and to contribute with new evidence to refine the classification of this substitution according to ACMG/AMP guidelines. The presence of the variant was screened in patients and controls. RT-PCR was performed in order to compare the transcriptional profiles of two variant carriers and ten non-carrier controls. In addition, allele-specific expression was assessed. No differences in variant frequency were detected between patients and controls. The RNA assay confirmed the presence of the shorter transcript lacking exons 2–9, but it was detected both in carriers and non-carriers. Furthermore, allelic imbalance was discarded and no significant differences in the proportion of full-length and shorter transcript were detected between carriers and controls. The shorter transcript detected corresponds to BARD1 isoform η, constituted by exons 1, 10 and 11. Our results support that this transcript is a constitutive splicing product rather than an aberrant transcript caused by BARD1 c.1977A>G variant, and for this reason this variant should be considered as likely benign following ACMG/AMP guidelines.Paula RofesMarta PinedaLídia FeliubadalóMireia MenéndezRafael de CidCarolina GómezEva MontesGabriel CapelláJoan BrunetJesús del ValleConxi LázaroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paula Rofes Marta Pineda Lídia Feliubadaló Mireia Menéndez Rafael de Cid Carolina Gómez Eva Montes Gabriel Capellá Joan Brunet Jesús del Valle Conxi Lázaro RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant
description	Abstract Case–control studies have shown an association of BARD1 with hereditary breast and/or ovarian cancer (HBOC) predisposition. BARD1 alternatively spliced isoforms are abundant and some are highly expressed in different cancer types. In addition, a number of BARD1 germline pathogenic variants have been reported among HBOC patients. In previous reports, BARD1 c.1977A>G variant has been classified as pathogenic since it produces a frameshift transcript lacking exons 2 to 9. In the present study, we sought to validate the mRNA splicing results previously published and to contribute with new evidence to refine the classification of this substitution according to ACMG/AMP guidelines. The presence of the variant was screened in patients and controls. RT-PCR was performed in order to compare the transcriptional profiles of two variant carriers and ten non-carrier controls. In addition, allele-specific expression was assessed. No differences in variant frequency were detected between patients and controls. The RNA assay confirmed the presence of the shorter transcript lacking exons 2–9, but it was detected both in carriers and non-carriers. Furthermore, allelic imbalance was discarded and no significant differences in the proportion of full-length and shorter transcript were detected between carriers and controls. The shorter transcript detected corresponds to BARD1 isoform η, constituted by exons 1, 10 and 11. Our results support that this transcript is a constitutive splicing product rather than an aberrant transcript caused by BARD1 c.1977A>G variant, and for this reason this variant should be considered as likely benign following ACMG/AMP guidelines.
format	article
author	Paula Rofes Marta Pineda Lídia Feliubadaló Mireia Menéndez Rafael de Cid Carolina Gómez Eva Montes Gabriel Capellá Joan Brunet Jesús del Valle Conxi Lázaro
author_facet	Paula Rofes Marta Pineda Lídia Feliubadaló Mireia Menéndez Rafael de Cid Carolina Gómez Eva Montes Gabriel Capellá Joan Brunet Jesús del Valle Conxi Lázaro
author_sort	Paula Rofes
title	RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant
title_short	RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant
title_full	RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant
title_fullStr	RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant
title_full_unstemmed	RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant
title_sort	rna assay identifies a previous misclassification of bard1 c.1977a>g variant
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e832dc5f39ae4707b42c6464ddf64fb7
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RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant

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