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Hum Mutat. 2018 Dec;39(12):2025-2039. doi: 10.1002/humu.23652. Epub 2018 Sep 24.

BRCA1 and BRCA2 5' noncoding region variants identified in breast cancer patients alter promoter activity and protein binding.

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School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Section of Molecular Genetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
University of Western Ontario, Department of Biochemistry, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
CytoGnomix Inc., London, Ontario, Canada.
Center for Medical Genetics, Ghent University Hospital, and Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.
Service de Génétique, Department de Biologie des Tumeurs, Institut Curie, Paris, France.
Department of oncology, Center for Translational Oncology, Cancer Institute of the State of São Paulo - ICESP, São Paulo, Brazil.
A.C.Camargo Cancer Center, São Paulo, Brazil.
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Area of Clinical and Molecular Genetics, University Hospital Vall d'Hebron (UHVH), Barcelona, Spain.
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Gustave Roussy, Villejuif, France.
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.


The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.


BRCA1; BRCA2; breast cancer; promoter; transcription; variants of unknown clinical significance (VUS)

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