The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Colombo M, Lopez-Perolio I, Meeks HD, Caleca L, Parsons MT, Li H, De Vecchi G, Tudini E, Foglia C, Mondini P, Manoukian S, Behar R, Garcia EBG, Meindl A, Montagna M, Niederacher D, Schmidt AY, Varesco L, Wappenschmidt B, Bolla MK, Dennis J, Michailidou K, Wang Q, Aittomaki K, Andrulis IL, Anton-Culver H, Arndt V, Beckmann M, Beeghly-Fadel A, Benitez J, Boeckx B, Bogdanova NV, Bojesen SE, Bonanni B, Brauch H, Brenner H, Burwinkel B, Chang-Claude J, Conroy DM, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Dork T, Eriksson M, Fasching P, Figueroa J, Fletcher O, Flyger H, Gabrielson M, Garcia-Closas M, Giles GG, Gonzalez-Neira A, Guenel P, Haiman CA, Hall P, Hamann U, Hartman M, Hauke J, Hollestelle A, Hopper JL, Jakubowska A, Jung A, Kosma VM, Lambrechts D, Le Marchand L, Lindblom A, Lubinski J, Mannermaa A, Margolin S, Miao H, Milne RL, Neuhausen SL, Nevanlinna H, Olson JE, Peterlongo P, Peto J, Pylkas K, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneeweiss A, Schoemaker MJ, See MH, Southey MC, Swerdlow A, Teo SH, Toland AE, Tomlinson I, Truong T, Van Asperen CJ, Van Den Ouweland AMW, Van Der Kolk LE, Winqvist R, Yannoukakos D, Zheng W, Dunning AM, Easton DF, Henderson A, Hogervorst FBL, Izatt L, Offitt K, Side LE, Van Rensburg EJ, Mcguffog L, Antoniou AC, Chenevix-Trench G, Spurdle AB, Goldgar DE, De La Hoya M, Radice P (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 39

Pages Range: 729-741

Journal Issue: 5

DOI: 10.1002/humu.23411

Abstract

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

Authors with CRIS profile

Involved external institutions

QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of California Irvine United States (USA) (US) Helsingin yliopisto / University of Helsinki Finland (FI) Istituto di ricovero e cura a carattere scientifico (IRCCS) Italy (IT) Mount Sinai Hospital (MSH) Canada (CA) Ludwig-Maximilians-Universität (LMU) Germany (DE) University of Cambridge United Kingdom (GB) Vanderbilt University United States (USA) (US) Hospital Clínico San Carlos Spain (ES) Copenhagen University Hospital Denmark (DK) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Memorial Sloan Kettering Cancer Center United States (USA) (US) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) Mayo Clinic United States (USA) (US) Princess Anne Hospital United Kingdom (GB) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) University of Oxford United Kingdom (GB) The Institute of Cancer Research (ICR) United Kingdom (GB) Guy's and St Thomas' (NHS Foundation Trust) United Kingdom (GB) European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) Newcastle upon Tyne Hospitals NHS Foundation Trust United Kingdom (GB) Robert-Bosch-Krankenhaus Germany (DE) University of Malaya (UM) / Universiti Malaya Malaysia (MY) University of Eastern Finland Finland (FI) City of Hope Medical Center United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Cancer Council Victoria Australia (AU) École Polytechnique - Université Paris-Saclay France (FR) Ruprecht-Karls-Universität Heidelberg Germany (DE) London School of Hygiene and Tropical Medicine United Kingdom (GB) Oulun Yliopisto / University of Oulo Finland (FI) King’s College London United Kingdom (GB) National Centre for Scientific Research (NCSR) "Demokritos" Greece (GR) University of Sheffield United Kingdom (GB) Karolinska Institute Sweden (SE) Universitätsklinikum Köln Germany (DE) Leiden University Netherlands (NL) National University of Singapore (NUS) Singapore (SG) University of Edinburgh United Kingdom (GB) Erasmus University Medical Center (MC) Netherlands (NL) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) National Cancer Institute (NCI) United States (USA) (US) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) The University of Melbourne Australia (AU) University of Southern California (USC) United States (USA) (US) Heinrich-Heine-Universität Düsseldorf Germany (DE) University of Utah United States (USA) (US) University of Hawaii (U.H.) United States (USA) (US) Ohio State University United States (USA) (US) Maastricht University Medical Center (UMC+) Netherlands (NL) University of Copenhagen Denmark (DK) Ospedale San Martino (IRCCS AOU) Italy (IT) Istituto Oncologico Veneto (IOV), IRCCS Italy (IT) University of Pretoria South Africa (ZA)

How to cite

APA:

Colombo, M., Lopez-Perolio, I., Meeks, H.D., Caleca, L., Parsons, M.T., Li, H.,... Radice, P. (2018). The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity. Human Mutation, 39(5), 729-741. https://doi.org/10.1002/humu.23411

MLA:

Colombo, Mara, et al. "The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity." Human Mutation 39.5 (2018): 729-741.

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