BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

kConFab/AOCS Investigators; NBCS Collaborators

doi:10.1158/0008-5472.CAN-16-2568

BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

kConFab/AOCS Investigators
, NBCS Collaborators

Institute of Human Genetics

Mayo Clinic Rochester, MN
Leiden University
Institut Curie
The University of Chicago
University of Utah School of Medicine
Helsinki University Hospital
Samuel Lunenfeld Research Institute
University of Toronto
University of California, Irvine
German Cancer Research Center
Friedrich-Alexander University Erlangen-Nürnberg
Centro de Investigación en Red de Enfermedades Raras
Centre for Biomedical Research on Rare Diseases (CIBERER)
Hannover Medical School
Copenhagen University Hospital – Herlev and Gentofte
University of Copenhagen
University of Cambridge
Oslo University Hospital-Radiumhospitalet
University of Oslo
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
University of Tübingen
International Agency for Research on Cancer
Antoni van Leeuwenhoek Hospital
University Hospitals Leuven
Ruhr University Bochum
Heidelberg University
University of Hamburg
Queensland Institute of Medical Research
National University of Singapore
Seoul National University
Erasmus University Rotterdam
University of Sheffield
Karolinska Institutet
London School of Hygiene and Tropical Medicine
University of California at Los Angeles
University of Edinburgh
National Cancer Institute (NCI)
Cancer Council Victoria
Centre for Epidemiology and Biostatistics
Occupational and Social Determinants of Health
Keck School of Medicine of USC
National University Health System
Erasmus MC Cancer Institute
Aichi Cancer Center Hospital and Research Institute
Nagoya University
Pomeranian Medical University in Szczecin
University of Eastern Finland
Oslo University Hospital
Sime Darby Medical Centre
University of Malaya
Vesalius Research Center
KU Leuven
University of Hawaii Cancer Center
University of Warwick
Masaryk Memorial Cancer Institute
Cyprus Institute of Neurology and Genetics
University of Manchester
Beckman Research Institute of City of Hope
University of Groningen
FIRC Institute of Molecular Oncology
University of Oulu
Northern Finland Laboratory Centre Oulu
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
Shaukat Khanum Memorial Cancer Hospital and Research Centre
The National Cancer Institute
Guy’s Hospital
Institute of Cancer Research
China Medical University Taichung
Academia Sinica - Institute of Biomedical Sciences
Vanderbilt University
University of Melbourne
University of Oxford
National Taiwan University Hospital
Shanghai Municipal Center for Disease Control and Prevention
University of Sydney
University of Otago
Demokritos National Centre for Scientific Research
Ghent University Hospital
Liguria Cancer Registry c/o IST/UNIGE
Moffitt Cancer Center
University of South Florida, Tampa
Huntsman Cancer Institute

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	2789-2799
Number of pages	11
Journal	Cancer Research
Volume	77
Issue number	11
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-2568
State	Published - 01 Jun 2017

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SDG 3 Good Health and Well-being

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10.1158/0008-5472.CAN-16-2568

Cite this

@article{5de00cc834ea46feb744ed33f3e99ad2,

title = "BRCA2 hypomorphic missense variants confer moderate risks of breast cancer",

abstract = "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.",

author = "\{kConFab/AOCS Investigators\} and \{NBCS Collaborators\} and Hermela Shimelis and Mesman, \{Romy L.S.\} and \{Von Nicolai\}, Catharina and Asa Ehlen and Lucia Guidugli and Charlotte Martin and Call{\'e}ja, \{Fabienne M.G.R.\} and Huong Meeks and Emily Hallberg and Jamie Hinton and Jenna Lilyquist and Chunling Hu and Aalfs, \{Cora M.\} and Kristiina Aittom{\"a}ki and Irene Andrulis and Hoda Anton-Culver and Volker Arndt and Beckmann, \{Matthias W.\} and Javier Benitez and Bogdanova, \{Natalia V.\} and Bojesen, \{Stig E.\} and Bolla, \{Manjeet K.\} and Borresen-Dale, \{Anne Lise\} and Hiltrud Brauch and Paul Brennan and Hermann Brenner and Annegien Broeks and Barbara Brouwers and Thomas Br{\"u}ning and Barbara Burwinkel and Jenny Chang-Claude and Georgia Chenevix-Trench and Cheng, \{Ching Yu\} and Choi, \{Ji Yeob\} and Coll{\'e}e, \{J. Margriet\} and Angela Cox and Cross, \{Simon S.\} and Kamila Czene and Hatef Darabi and Joe Dennis and Thilo D{\"o}rk and Isabel Dos-Santos-Silva and Dunning, \{Alison M.\} and Fasching, \{Peter A.\} and Jonine Figueroa and Henrik Flyger and Montserrat Garc{\'i}a-Closas and Giles, \{Graham G.\} and Gord Glendon and Diana Torres",

note = "Publisher Copyright: {\textcopyright}2017 AACR.",

year = "2017",

month = jun,

day = "1",

doi = "10.1158/0008-5472.CAN-16-2568",

language = "English",

volume = "77",

pages = "2789--2799",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

TY - JOUR

T1 - BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

AU - kConFab/AOCS Investigators

AU - NBCS Collaborators

AU - Shimelis, Hermela

AU - Mesman, Romy L.S.

AU - Von Nicolai, Catharina

AU - Ehlen, Asa

AU - Guidugli, Lucia

AU - Martin, Charlotte

AU - Calléja, Fabienne M.G.R.

AU - Meeks, Huong

AU - Hallberg, Emily

AU - Hinton, Jamie

AU - Lilyquist, Jenna

AU - Hu, Chunling

AU - Aalfs, Cora M.

AU - Aittomäki, Kristiina

AU - Andrulis, Irene

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Beckmann, Matthias W.

AU - Benitez, Javier

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Borresen-Dale, Anne Lise

AU - Brauch, Hiltrud

AU - Brennan, Paul

AU - Brenner, Hermann

AU - Broeks, Annegien

AU - Brouwers, Barbara

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Cheng, Ching Yu

AU - Choi, Ji Yeob

AU - Collée, J. Margriet

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Dos-Santos-Silva, Isabel

AU - Dunning, Alison M.

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - García-Closas, Montserrat

AU - Giles, Graham G.

AU - Glendon, Gord

AU - Torres, Diana

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85020735683

U2 - 10.1158/0008-5472.CAN-16-2568

DO - 10.1158/0008-5472.CAN-16-2568

M3 - Article

C2 - 28283652

AN - SCOPUS:85020735683

SN - 0008-5472

VL - 77

SP - 2789

EP - 2799

JO - Cancer Research

JF - Cancer Research

IS - 11

ER -

BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

Abstract

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