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Cited by 239BRCA gene mutations in cancerRNA Research and SplicingGenomics and Rare Diseases

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Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants

Houdayer, Claude, Caux-Moncoutier, Virginie, Krieger, Sophie, Barrois, Michel, Bonnet, Françoise, Bourdon, Violaine, Bronner, Myriam, Buisson, Monique, Coulet, Florence, Gaildrat, Pascaline, Lefol, Cédrick, Léone, Mélanie, Mazoyer, Sylvie, Muller, Danielle, Remenieras, Audrey, Révillion, Françoise, Rouleau, Etienne, Sokolowska, Joanna, Vert, Jean-Philippe, Lidereau, Rosette, Soubrier, Florent, Sobol, Hagay, Sevenet, Nicolas, Bressac-de Paillerets, Brigitte, Hardouin, Agnès, Tosi, Mario, Sinilnikova, Olga M., Stoppa-Lyonnet, Dominique·2012·Human Mutation
DOI 10.1002/humu.22101
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Abstract

Assessing the impact of variants of unknown significance (VUS) on splicing is a key issue in molecular diagnosis. This impact can be predicted by in silico tools, but proper evaluation and user guidelines are lacking. To fill this gap, we embarked upon the largest BRCA1 and BRCA2 splice study to date by testing 272 VUSs (327 analyses) within the BRCA splice network of Unicancer. All these VUSs were analyzed by using six tools (splice site prediction by neural network, splice site finder (SSF), MaxEntScan (MES), ESE finder, relative enhancer and silencer classification by unanimous enrichment, and human splicing finder) and the predictions obtained were compared with transcript analysis results. Combining MES and SSF gave 96% sensitivity and 83% specificity for VUSs occurring in the vicinity of consensus splice sites, that is, the surrounding 11 and 14 bases for the 5' and 3' sites, respectively. This study was also an opportunity to define guidelines for transcript analysis along with a tentative classification of splice variants. The guidelines drawn from this large series should be useful for the whole community, particularly in the context of growing sequencing capacities that require robust pipelines for variant interpretation.

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Metadata

Authors
Houdayer, C., Caux-Moncoutier, V., Krieger, S., Barrois, M., Bonnet, F., Bourdon, V., Bronner, M., Buisson, M., Coulet, F., Gaildrat, P., Lefol, C., Léone, M., Mazoyer, S., Muller, D., Remenieras, A., Révillion, F., Rouleau, E., Sokolowska, J., Vert, J.-P., Lidereau, R., Soubrier, F., Sobol, H., Sevenet, N., Bressac-de Paillerets, B., Hardouin, A., Tosi, M., Sinilnikova, O. M., & Stoppa-Lyonnet, D.
Affiliations
  • Sorbonne Paris Cité (FR)
  • Centre François Baclesse (FR)
  • Institut Gustave Roussy (FR)
  • Inserm (FR)
  • Institut Paoli-Calmettes (FR)
  • Centre Hospitalier Régional et Universitaire de Nancy (FR)
  • Lyon 1 Université (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Hôpital René Huguenin (FR)
  • Institut Strauss (FR)
Corresponding author
Houdayer, Claude
ORCID
Venue
Human Mutation
Publisher
Hindawi Limited
Published
2012-05-11
Volume
33
Issue
8
Pages
1228-1238
ISSN
1059-7794 (ISSN-L)
DOI
10.1002/humu.22101
OpenAlex
W1975196485
Cited by
239
References
0
Citations by year
2026: 3 · 2025: 5 · 2024: 11 · 2023: 6 · 2022: 25 · 2021: 27 · 2020: 22 · 2019: 23 · 2018: 27 · 2017: 23 · 2016: 14 · 2015: 22 · 2014: 11 · 2013: 17 · 2012: 3
FWCI
10.21
Type
journal article
Language
en
Open access
closed
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1208 d)
Locations
  • Human Mutation (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
BRCA1, BRCA2, variants of uncertain significance, splicing, splice site prediction, in silico tools, transcript analysis, variant interpretation, molecular diagnosis
MeSH terms
Exons, Female, Humans, RNA Splicing, BRCA1 Protein, BRCA2 Protein, Pathology, Molecular

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