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Grant support

Supported by the Carlos III National Health Institute funded by European Fundfor Regional Development grantsPI19/00553, PI16/00563, PI16/01898, and SAF2015-68016-R, Centro de Investigacion Biomedica en Red de Cancer, and Government of Catalonia (PERIS_MedPerCan and URDCat projects) grants 2017SGR1282 and 2017SGR496.

Analysis of institutional authors

Del Valle Dominguez, JesusAuthorRofes PAuthorMenendez MAuthorGonzález SAuthorTornero EAuthorBrunet JAuthorTeule AAuthorCapella GAuthorFeliubadalo LAuthorPineda MAuthorLazaro CCorresponding Author

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October 21, 2020
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Article

Improving genetic testing in hereditary cancer by RNA analysis: tools to prioritize splicing studies and challenges in applying American College of Medical Genetics and Genomics guidelines

Publicated to:Journal Of Molecular Diagnostics. 22 (12): 1453-1468 - 2020-12-01 22(12), DOI: 10.1016/j.jmoldx.2020.09.007

Authors: Rofes, P; Menéndez, M; González, S; Tornero, E; Gómez, C; Vargas-Parra, G; Montes, E; Salinas, M; Solanes, A; Brunet, J; Teulé, A; Capellá, G; Feliubadaló, L; del Valle, J; Pineda, M; Lázaro, C

Affiliations

Bellvitge Inst Biomed Res, Oncobell Program, Barcelona, Spain - Author
Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain - Author
Ctr Invest Biomed Red Canc, Madrid, Spain - Author

Abstract

RNA analyses are a potent tool to identify spliceogenic effects of DNA variants, although they are time-consuming and cannot always be performed. We present splicing assays of 20 variants that represent a variety of mutation types in 10 hereditary cancer genes and attempt to incorporate these results into American College of Medical Genetics and Genomics (ACMG) classification guidelines. We selected 16 single-nucleotide variants, 3 exon duplications, and 1 single-exon deletion prioritized by in silico algorithms. RNA was extracted from short-term lymphocyte cultures to perform RT-PCR and Sanger sequencing, and allele-specific expression was assessed whenever possible. We detected aberrant transcripts in 14 variants (70%). We faced the difficulty of variant interpretation comparing old classification standards to generic ACMG guidelines and devised a proposal to weight functional analyses at RNA level. According to the ACMG guidelines, only 12 variants were reclassified as pathogenic/likely pathogenic because the other two variants did not have enough evidence. Our study highlights the importance of RNA studies to improve variant classification. However, it also indicates the challenge of incorporating these results into generic ACMG guidelines and the need to refine these criteria gene specifically. Nevertheless, 60% of variants were reclassified, thus improving genetic counseling and surveillance for carriers of these variants.Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Keywords

AdultAgar gel electrophoresisAgedAlleleAllelesArticleAtm proteinBrca1Brca1 proteinBrca2 proteinBreastBreast cancerCase reportCheckpoint kinase 2Cohort analysisCohort studiesComputer simulationControlled studyCopy number variationDna copy number variationsExonExon skippingExonsFamilial adenomatous polyposisFemaleFrameshift mutationGene expressionGene mutationGenetic predispositionGenetic predisposition to diseaseGenetic screeningGenetic testingGenetic variabilityGeneticsGenome, humanGenomicsGuidelinesHereditary tumor syndromeHigh throughput sequencingHigh-throughput nucleotide sequencingHumanHuman genomeHumansIntronIntron retentionIntronsLymphocyte cultureMajor clinical studyMaleMessenger rnaMethionineMiddle agedMultiplex ligation dependent probe amplificationMutationsNeoplastic syndromes, hereditaryOvarian-cancerOvary cancerPanelsPolymorphism, single nucleotidePractice guidelinePractice guidelines as topicPredictionProceduresProteinProtein p53Rad51c proteinReal time polymerase chain reactionRecommendationsRnaRna splicingRna, messengerSequence analysisSequence analysis, rnaSequence variantsSmad4 proteinUnclassified drugYoung adult

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of Molecular Diagnostics due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 13/77, thus managing to position itself as a Q1 (Primer Cuartil), in the category Pathology.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 2.59, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-18, the following number of citations:

  • WoS: 8
  • Scopus: 9
  • Europe PMC: 5

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-18:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 33.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 39 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 9.5.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (ROFES TORRES, PAULA) and Last Author (Lazaro Garcia, Concepcion).

the author responsible for correspondence tasks has been Lazaro Garcia, Concepcion.