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Hum Mutat. 2018 Apr;39(4):515-526. doi: 10.1002/humu.23390. Epub 2018 Jan 22.

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11.

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Department of Basic Medical Sciences, Ghent University, Ghent, Belgium.
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
BC Cancer Agency, Vancouver, British Columbia, Canada.
Cancer Genetics and Genomics Laboratory, Department of Pathology and Laboratory Medicine, BC Cancer Agency, Vancouver, British Columbia, Canada.
Provincial Medical Genetics Program, Eastern Health, St. John's, Newfoundland and Labrador, Canada.
Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.
Familial Cancer Program, University of Vermont Medical Center, Burlington, Vermont, United States.
Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain.
Molecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.


For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5' breakpoint in intron 4; 3' breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G > C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.


BRCA1/2; alternative splicing; cDNA analysis; in silico prediction tools; learning algorithms

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