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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity
Human Mutation, Volume 39, No. 5, Year 2018
Notification
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Description
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. © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC5947288/bin/HUMU-39-729-s001.docx
https://efashare.b-cdn.net/share/pmc/articles/PMC5947288/bin/HUMU-39-729-s002.docx
Authors & Co-Authors
Meeks, Huong D.
United States, Salt Lake City
The University of Utah
Caleca, L.
Italy, Milan
Fondazione Irccs Istituto Nazionale Dei Tumori, Milan
Parsons, Michael T.
Australia, Brisbane
Qimr Berghofer Medical Research Institute
Li, Hongyan
United States, Salt Lake City
The University of Utah
Tudini, Emma
Australia, Brisbane
Qimr Berghofer Medical Research Institute
Manoukian, Siranoush
Italy, Milan
Fondazione Irccs Istituto Nazionale Dei Tumori, Milan
García, Encarna B.Gómez
Netherlands, Maastricht
Maastricht Universitair Medisch Centrum+
Meindl, Alfons
Germany, Munich
Ludwig-maximilians-universität München
Montagna, Marco
Italy, Padua
Istituto Oncologico Veneto Iov - Irccs
Niederacher, Dieter
Germany, Dusseldorf
Heinrich-heine-universität Düsseldorf
Varesco, Liliana
Italy, Genoa
Irccs San Martino Polyclinic Hospital
Wappenschmidt, Barbara
Germany, Koln
Uniklinik Köln
Bolla, Manjeet K.
United Kingdom, Cambridge
University of Cambridge
Dennis, Joe G.
United Kingdom, Cambridge
University of Cambridge
Michailidou, Kyriaki
United Kingdom, Cambridge
University of Cambridge
Cyprus, Nicosia
Cyprus Institute of Neurology and Genetics
Wang, Qin
United Kingdom, Cambridge
University of Cambridge
Aittomäki, Kristiina A.U.
Finland, Helsinki
Helsingin Yliopisto
Andrulis, Irene L.
United States, New York
The Mount Sinai Hospital
Canada, Toronto
University of Toronto
Anton-Culver, Hoda
United States, Irvine
University of California, Irvine
Arndt, Volker
Germany, Heidelberg
German Cancer Research Center
Beckmann, Matthias Wilhelm
Unknown Affiliation
Benit́ez, Javier J.
Spain, Madrid
Centro Nacional de Investigaciones Oncológicas
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Raras
Boeckx, Bram
Belgium, Ghent
Vlaams Instituut Voor Biotechnologie
Belgium, Leuven
Ku Leuven
Bogdanova, Natalia Valerijevna
Germany, Hannover
Hannover Medical School
Belarus, Minsk
Research Institute of Oncology and Medical Radiology of the Ministry of Health of the Byelorussian Ssr
Bojesen, Stig Egil
Denmark, Copenhagen
Copenhagen University Hospital
Denmark, Copenhagen
Københavns Universitet
Bonanni, Bernardo
Italy, Milan
Istituto Europeo Di Oncologia
Brauch, Hiltrud B.
Germany, Stuttgart
Dr. Margarete Fischer-bosch-institut Für Klinische Pharmakologie
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Heidelberg
German Cancer Research Center
Brenner, Hermann
Germany, Heidelberg
German Cancer Research Center
Burwinkel, Barbara
Germany, Heidelberg
Universität Heidelberg
Germany, Heidelberg
German Cancer Research Center
Chang-Claude, Jenny C.
Germany, Heidelberg
German Cancer Research Center
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Couch, Fergus J.
United States, Rochester
Mayo Clinic
Cox, Angela
United Kingdom, Sheffield
The University of Sheffield
Cross, Simon S.
United Kingdom, Sheffield
The University of Sheffield
Czene, Kamila
Sweden, Stockholm
Karolinska Institutet
Devilée, Peter P.
Netherlands, Leiden
Leids Universitair Medisch Centrum
Dörk, Thilo
Germany, Hannover
Hannover Medical School
Eriksson, Mikael
Sweden, Stockholm
Karolinska Institutet
Fasching, Peter Andreas
United States, Los Angeles
University of California, Los Angeles
Figueroa, Jonine D.
United Kingdom, Edinburgh
Edinburgh Medical School
United States, Rockville
National Cancer Institute Nci
Fletcher, Olivia
United Kingdom, London
The Institute of Cancer Research
Flyger, Henrik Lavlund
Denmark, Copenhagen
Copenhagen University Hospital
Gabrielson, Marike
Sweden, Stockholm
Karolinska Institutet
García-Closas, Montserrat
United States, Rockville
National Cancer Institute Nci
Giles, Graham G.
Australia, East Melbourne
Cancer Council Victoria
Australia, Melbourne
University of Melbourne
González-Neira, Anna
Spain, Madrid
Centro Nacional de Investigaciones Oncológicas
Guénel, Pascal
France, Paris
Inserm
Haiman, Christopher A.
United States, Los Angeles
University of Southern California
Hall, Per F.L.
Sweden, Stockholm
Karolinska Institutet
Hamann, Ute
Germany, Heidelberg
German Cancer Research Center
Hartman, Mikael L.
Singapore, Singapore City
National University of Singapore
Singapore, Singapore City
National University Health System
Hauke, Jan
Germany, Koln
Uniklinik Köln
Germany, Koln
Universität zu Köln
Hollestelle, Antoinette
Netherlands, Rotterdam
Erasmus Mc Cancer Institute
Hopper, John Llewelyn
Australia, Melbourne
University of Melbourne
Jakubowska, Anna
Poland, Szczecin
Pomeranian Medical University in Szczecin
Jung, Audrey Y.
Germany, Heidelberg
German Cancer Research Center
Kosma, Veli Matti
Finland, Kuopio
Itä-suomen Yliopisto
Finland, Kuopio
Kuopio University Hospital
Lambrechts, Diether
Belgium, Ghent
Vlaams Instituut Voor Biotechnologie
Belgium, Leuven
Ku Leuven
Le Marchand, Loic̈
United States, Honolulu
University of Hawaiʻi Cancer Center
Lindblöm, Annika
Sweden, Stockholm
Karolinska Institutet
Lubiński, Jan
Poland, Szczecin
Pomeranian Medical University in Szczecin
Mannermaa, Arto Msci
Finland, Kuopio
Itä-suomen Yliopisto
Finland, Kuopio
Kuopio University Hospital
Margolin, Sara J.
Sweden, Stockholm
Södersjukhuset
Hui, Miao
Singapore, Singapore City
National University of Singapore
Milne, Roger L.
Australia, East Melbourne
Cancer Council Victoria
Australia, Melbourne
University of Melbourne
Floris, Giuseppe L.
United States, Duarte
City of Hope National Med Center
Nevanlinna, Heli A.
Finland, Helsinki
Helsingin Yliopisto
Olson, Janet E.
United States, Rochester
Mayo Clinic
Peterlongo, Paolo
Italy, Milan
Fondazione Ifom Istituto Firc Di Oncologia Molecolare
Peto, Julian
United Kingdom, London
London School of Hygiene & Tropical Medicine
Pylkäs, Katri
Finland, Oulu
Oulun Yliopisto
Sawyer, Elinor J.
United Kingdom, London
King's College London
Schmidt, Marjanka K.
Netherlands, Amsterdam
The Netherlands Cancer Institute
Schmutzler, Rita Katharina
Germany, Koln
Uniklinik Köln
Germany, Koln
Universität zu Köln
Schneeweiß, Andreas
Germany, Heidelberg
Universität Heidelberg
Germany, Heidelberg
German Cancer Research Center
Schoemaker, Minouk J.
United Kingdom, London
The Institute of Cancer Research
Southey, Melissa Caroline
Australia, Melbourne
University of Melbourne
Swerdlow, Anthony J.
United Kingdom, London
The Institute of Cancer Research
Teo, Soo Hwang
Malaysia, Kuala Lumpur
University of Malaya Medical Centre
Toland, Amanda Ewart
United States, Columbus
The Ohio State University
Tomlinson, Ian P.M.
United Kingdom, Oxford
Nihr Oxford Biomedical Research Centre
Truong, Thérèse
France, Paris
Inserm
van Asperen, Christi J.
Netherlands, Leiden
Universiteit Leiden
van den Ouweland, Ans M.W.
Netherlands, Rotterdam
Erasmus Mc
Winqvist, Robert
Finland, Oulu
Oulun Yliopisto
Yannoukakos, Drakoulis
Greece, Athens
National Centre for Scientific Research Demokritos
Zheng, Wei
United States, Nashville
Vanderbilt University School of Medicine
Dunning, Alison M.
United Kingdom, Cambridge
University of Cambridge
Easton, Douglas F.
United Kingdom, Cambridge
University of Cambridge
Henderson, Alex
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Hogervorst, Frans B.L.
Netherlands, Amsterdam
The Netherlands Cancer Institute
Izatt, Louise
United Kingdom, London
Guy's and st Thomas' Nhs Foundation Trust
Side, Lucy E.
United Kingdom, Southampton
Princess Anne Hospital
van Rensburg, Elizabeth J.
South Africa, Pretoria
University of Pretoria
McGuffog, Lesley
United Kingdom, Cambridge
University of Cambridge
Antoniou, Antonis C.
United Kingdom, Cambridge
University of Cambridge
Chenevix-Trench, Georgia
Australia, Brisbane
Qimr Berghofer Medical Research Institute
Spurdle, Amanda B.
Australia, Brisbane
Qimr Berghofer Medical Research Institute
Goldgar, David E.
United States, Salt Lake City
The University of Utah
de la Hoya, Miguel
Spain, Madrid
Centro de Investigación Biomédica en Red de Cáncer
Radice, Paolo
Italy, Milan
Fondazione Irccs Istituto Nazionale Dei Tumori, Milan
Statistics
Citations: 18
Authors: 100
Affiliations: 70
Identifiers
Doi:
10.1002/humu.23411
ISSN:
10597794
Research Areas
Cancer
Genetics And Genomics
Study Design
Case-Control Study
Study Approach
Quantitative