BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer
Authors: Shimelis Hermela , Mesman Romy L.S. , Von Nicolai Catharina , Ehlen Asa , Guidugli Lucia , Martin Charlotte , Calléja Fabienne M.G.R. , Meeks Huong , Hallberg Emily , Hinton Jamie , Lilyquist Jenna , Hu Chunling , Aalfs Cora M. , Aittomäki Kristiina , Andrulis Irene , Anton-Culver Hoda , Arndt Volker , Beckmann Matthias W. , Benitez Javier , Bogdanova Natalia V. , Bojesen Stig E. , Bolla Manjeet K. , Borresen-Dale Anne-Lise , Brauch Hiltrud , Brennan Paul , Brenner Hermann , Broeks Annegien , Brouwers Barbara , Brüning Thomas , Burwinkel Barbara , Chang-Claude Jenny , Chenevix-Trench Georgia , Cheng Ching-Yu , Choi Ji-Yeob , Collée J. Margriet , Cox Angela , Cross Simon S. , Czene Kamila , Darabi Hatef , Dennis Joe , Dörk Thilo , dos-Santos-Silva Isabel , Dunning Alison M. , Fasching Peter A. , Figueroa Jonine , Flyger Henrik , García-Closas Montserrat , Giles Graham G. , Glendon Gord , Guénel Pascal , Haiman Christopher A. , Hall Per , Hamann Ute , Hartman Mikael , Hogervorst Frans B. , Hollestelle Antoinette , Hopper John L. , Ito Hidemi , Jakubowska Anna , Kang Daehee , Kosma Veli-Matti , Kristensen Vessela , Lai Kah-Nyin , Lambrechts Diether , Marchand Loic Le , Li Jingmei , Lindblom Annika , Lophatananon Artitaya , Lubinski Jan , Machackova Eva , Mannermaa Arto , Margolin Sara , Marme Frederik , Matsuo Keitaro , Miao Hui , Michailidou Kyriaki , Milne Roger L. , Muir Kenneth , Neuhausen Susan L. , Nevanlinna Heli , Olson Janet E. , Olswold Curtis , Oosterwijk Jan J.C. , Osorio Ana , Peterlongo Paolo , Peto Julian , Pharoah Paul D.P. , Pylkäs Katri , Radice Paolo , Rashid Muhammad Usman , Rhenius Valerie , Rudolph Anja , Sangrajrang Suleeporn , Sawyer Elinor J. , Schmidt Marjanka K. , Schoemaker Minouk J. , Seynaeve Caroline , Shah Mitul , Shen Chen-Yang , Shrubsole Martha , Shu Xiao-Ou , Slager Susan , Southey Melissa C. , Stram Daniel O. , Swerdlow Anthony , Teo Soo H. , Tomlinson Ian , Torres Diana , Truong Thérèse , van Asperen Christi J. , van der Kolk Lizet E. , Wang Qin , Winqvist Robert , Wu Anna H. , Yu Jyh-Cherng , Zheng Wei , Zheng Ying , Leary Jennifer , Walker Logan , Foretova Lenka , Fostira Florentia , Claes Kathleen B.M. , Varesco Liliana , Moghadasi Setareh , Easton Douglas F. , Spurdle Amanda , Devilee Peter , Vrieling Harry , Monteiro Alvaro N.A. , Goldgar David E. , Carreira Aura , Vreeswijk Maaike P.G. , Couch Fergus J. 
Published: March 2017

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&gt;C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G&gt;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&gt;A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G&gt;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.