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. 2017 Jun 1;77(11):2789-2799.
doi: 10.1158/0008-5472.CAN-16-2568. Epub 2017 Mar 10.

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Hermela Shimelis  1 Romy L S Mesman  2 Catharina Von Nicolai  3 Asa Ehlen  3 Lucia Guidugli  4 Charlotte Martin  5 Fabienne M G R Calléja  2 Huong Meeks  6 Emily Hallberg  7 Jamie Hinton  7 Jenna Lilyquist  7 Chunling Hu  1 Cora M Aalfs  8 Kristiina Aittomäki  9 Irene Andrulis  10   11 Hoda Anton-Culver  12 Volker Arndt  13 Matthias W Beckmann  14 Javier Benitez  15   16 Natalia V Bogdanova  17   18 Stig E Bojesen  19   20   21 Manjeet K Bolla  22 Anne-Lise Borresen-Dale  23   24 Hiltrud Brauch  25   26   27 Paul Brennan  28 Hermann Brenner  13   27   29 Annegien Broeks  30 Barbara Brouwers  31   32 Thomas Brüning  33 Barbara Burwinkel  34   35 Jenny Chang-Claude  36   37 Georgia Chenevix-TrenchChing-Yu Cheng  38 Ji-Yeob Choi  39   40 J Margriet Collée  41 Angela Cox  42 Simon S Cross  43 Kamila Czene  44 Hatef Darabi  44 Joe Dennis  22 Thilo Dörk  18 Isabel Dos-Santos-Silva  45 Alison M Dunning  46 Peter A Fasching  14   47 Jonine Figueroa  48   49 Henrik Flyger  50 Montserrat García-Closas  49 Graham G Giles  51   52 Gord Glendon  10 Pascal Guénel  53 Christopher A Haiman  54 Per Hall  44 Ute Hamann  55 Mikael Hartman  56   57 Frans B Hogervorst  30 Antoinette Hollestelle  58 John L Hopper  52 Hidemi Ito  59   60 Anna Jakubowska  61 Daehee Kang  39   40   62 Veli-Matti Kosma  63   64   65 Vessela KristensenKah-Nyin Lai  66   67 Diether Lambrechts  68   69 Loic Le Marchand  70 Jingmei Li  44 Annika Lindblom  71 Artitaya Lophatananon  72 Jan Lubinski  61 Eva Machackova  73 Arto Mannermaa  63   64   65 Sara Margolin  74 Frederik Marme  34   75 Keitaro Matsuo  60   76 Hui Miao  56 Kyriaki Michailidou  22   77 Roger L Milne  51   52 Kenneth Muir  72   78 Susan L Neuhausen  79 Heli Nevanlinna  80 Janet E Olson  7 Curtis Olswold  7 Jan J C Oosterwijk  81 Ana Osorio  15   16 Paolo Peterlongo  82 Julian Peto  45 Paul D P Pharoah  22   46 Katri Pylkäs  83   84 Paolo Radice  85 Muhammad Usman Rashid  55   86 Valerie Rhenius  46 Anja Rudolph  36 Suleeporn Sangrajrang  87 Elinor J Sawyer  88 Marjanka K Schmidt  30 Minouk J Schoemaker  89   90 Caroline Seynaeve  58 Mitul Shah  46 Chen-Yang Shen  91   92 Martha Shrubsole  93 Xiao-Ou Shu  93 Susan Slager  7 Melissa C Southey  94 Daniel O Stram  54 Anthony Swerdlow  89   90 Soo H Teo  66   67 Ian Tomlinson  95 Diana Torres  55   96 Thérèse Truong  53 Christi J van Asperen  8 Lizet E van der Kolk  30 Qin Wang  22 Robert Winqvist  83   84 Anna H Wu  54 Jyh-Cherng Yu  97 Wei Zheng  93 Ying Zheng  98 Jennifer Leary  99 Logan Walker  100 Lenka Foretova  73 Florentia Fostira  101 Kathleen B M Claes  102 Liliana Varesco  103 Setareh Moghadasi  8 Douglas F Easton  22   46 Amanda Spurdle  104 Peter Devilee  2 Harry Vrieling  2 Alvaro N A Monteiro  105   106 David E Goldgar  107 Aura Carreira  3 Maaike P G Vreeswijk  2 Fergus J Couch  108   7 for kConFab/AOCS Investigatorsfor NBCS Collaborators
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Free PMC article

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Hermela Shimelis et al. Cancer Res. .
Free PMC article

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. Cancer Res; 77(11); 2789-99. ©2017 AACR.

Conflict of interest statement

Conflict of Interest: The authors disclose no potential conflicts of interest

Figures

Figure 1
Figure 1
BRCA2 p.Y3035S segregates with breast cancer in high risk families. Five of the most informative pedigrees are shown. Upper black quadrants reflect breast cancer status. Type of cancer and age at diagnosis are displayed. Variant status is indicated by “Y3035S”. (+), mutation positive; (−), mutation negative reflects results of genetic testing.
Figure 2
Figure 2
(A) HDR and ssDNA binding activity of BRCA2 p.Y3035S is reduced. (A) Activity of BRCA2 missense variants is shown as HDR fold change with standard error (SE) (of three independent measures of duplicates) on a scale of one to five. Solid lines represent 99.9% and 0.1% probability of pathogenicity. (B) Representative Electrophoretic Mobility Shift Assays (EMSA) of DNA-protein complexes formed by mixing increasing concentrations (0, 5, 10, 20 nM) of purified BRCA2 wildtype and mutant proteins with ssDNA. (C) Quantitation of the DNA-protein complex formation shown in Fig. 2B. Error bars represent SE derived from at least three independent experiments. Statistical difference between WT and mutant BRCA2 protein-DNA complexes formation was determined by two-sample t-test. **p<0.001; *p<0.05. WT, wildtype.
Figure 3
Figure 3
HR efficiency and PARP inhibitor sensitivity of mES cells expressing hBRCA2 variants. (A) GFP expression from the DR-GFP reporter was analyzed as a measure of HR activity. The percentage GFP positive cells for each variant was normalized to wildtype hBRCA2 expressing cells. Results represent the mean of three independent experiments with two independent pools of BAC clones tested per variant. Error bars represent SE of three independent experiments. Statistical significance is indicated by “ * ”. (B) Relative cell survival compared to untreated cells was determined by cell count after 48hr exposure to PARP inhibitor KU-0058948. Data represent the mean of three experiments using two independent pools of BAC clones. **p<0.001; *p<0.05. WT, wildtype.

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