BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Journal article

Publication Details

Author(s): Shimelis H, Mesman RLS, Von Nicolai C, Ehlen A, Guidugli L, Martin C, Calleja FMGR, Meeks H, Hallberg E, Hinton J, Lilyquist J, Hu C, Aalfs CM, Aittomaki K, Andrulis I, Anton-Culver H, Arndt V, Beckmann M, Benitez J, Bogdanova NV, Bojesen SE, Bolla MK, Borresen-Dale AL, Brauch H, Brennan P, Brenner H, Broeks A, Brouwers B, Bruning T, Burwinkel B, Chang-Claude J, Chenevix-Trench G, Cheng CY, Choi JY, Collee JM, Cox A, Cross SS, Czene K, Darabi H, Dennis J, Dork T, Dos-Santos-Silva I, Dunning AM, Fasching P, Figueroa J, Flyger H, Garcia-Closas M, Giles GG, Glendon G, Guenel P, Haiman CA, Hall P, Hamann U, Hartman M, Hogervorst FB, Hollestelle A, Hopper JL, Ito H, Jakubowska A, Kang D, Kosma VM, Kristensen V, Lai KN, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lophatananon A, Lubinski J, Machackova E, Mannermaa A, Margolin S, Marme F, Matsuo K, Miao H, Michailidou K, Milne RL, Muir K, Neuhausen SL, Nevanlinna H, Olson JE, Olswold C, Oosterwijk JJC, Osorio A, Peterlongo P, Peto J, Pharoah PDP, Pylkas K, Radice P, Rashid MU, Rhenius V, Rudolph A, Sangrajrang S, Sawyer EJ, Schmidt MK, Schoemaker MJ, Seynaeve C, Shah M, Shen CY, Shrubsole M, Shu XO, Slager S, Southey MC, Stram DO, Swerdlow A, Teo SH, Tomlinson I, Torres D, Truong T, Van Asperen CJ, Van Der Kolk LE, Wang Q, Winqvist R, Wu AH, Yu JC, Zheng W, Zheng Y, Leary J, Walker L, Foretova L, Fostira F, Claes KBM, Varesco L, Moghadasi S, Easton DF, Spurdle A, Devilee P, Vrieling H, Monteiro ANA, Goldgar DE, Carreira A, Vreeswijk MPG, Couch FJ
Journal: Cancer Research
Publication year: 2017
Volume: 77
Journal issue: 11
Pages range: 2789-2799
ISSN: 0008-5472


Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe

External institutions with authors

Aichi Cancer Center Research Institute
Antoni van Leeuwenhoek
Cancer Council Victoria
Cancer Research Initiatives Foundation (CARIF)
Center for Cancer Biology (CCB) (formerly Vesalius Research Center (VRC))
China Medical University (CMU) / 中國醫藥大學
City of Hope Medical Center
Copenhagen University Hospital
Cyprus Institute of Neurology and Genetics
Deutsches Krebsforschungszentrum (DKFZ)
École Polytechnique - Université Paris-Saclay
Erasmus University Medical Center
Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam
Fondazione IRCCS: Istituto Nazionale dei Tumori
Helsingin yliopisto / University of Helsinki
H. Lee Moffitt Cancer Center & Research Institute
IFOM - FIRC Institute of Molecular Oncology
Institut Curie
International Agency for Research on Cancer (IARC)
Karolinska Institute
King’s College London
Leiden University
London School of Hygiene and Tropical Medicine
Masaryk Memorial Cancer Institute (MMCI) / Masarykův onkologický ústav (MOÚ)
Mayo Clinic
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Mount Sinai Hospital (MSH)
Nagoya University / 名古屋大学
National Cancer Institute (NCI)
National Centre for Scientific Research (NCSR) "Demokritos"
National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院
National University of Singapore (NUS)
Ospedale San Martino (IRCCS AOU)
Oulun Yliopisto / University of Oulo
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Ruhr-Universität Bochum (RUB)
Ruprecht-Karls-Universität Heidelberg
Seoul National University (SNU) / 서울대학교
Shanghai Center For Disease Control And Prevention (SCDC)
Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO)
The Institute of Cancer Research (ICR)
The University of Melbourne
University Hospital Ghent
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University of California Irvine
University of Cambridge
University of Chicago
University of Eastern Finland
University of Edinburgh
University of Groningen / Rijksuniversiteit Groningen
University of Hawaii (U.H.)
University of Otago
University of Oxford
University of Sheffield
University of Southern California (USC)
University of Sydney
University of Utah
University of Warwick
Vanderbilt University

How to cite

Shimelis, H., Mesman, R.L.S., Von Nicolai, C., Ehlen, A., Guidugli, L., Martin, C.,... Couch, F.J. (2017). BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. Cancer Research, 77(11), 2789-2799.

Shimelis, Hermela, et al. "BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer." Cancer Research 77.11 (2017): 2789-2799.


Last updated on 2019-26-03 at 10:08