BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

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

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 to wildtype. 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.