University of Oulu

Colombo M, Lòpez‐Perolio I, Meeks HD, et al. The BRCA2 c.68‐7T > A variant is not pathogenic: a model for clinical calibration of spliceogenicity. Human Mutation. 2018;39:729–741. https://doi.org/10.1002/humu.23411

The BRCA2 c.68‐7T > A variant is not pathogenic : a model for clinical calibration of spliceogenicity

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Author: Colombo, Mara1; Lopez-Perolio, Irene2; Meeks, Huong D.3;
Caleca, Laura1; Parsons, Michael T.4; Li, Hongyan3; De Vecchi, Giovanna1; Tudini, Emma4; Foglia, Claudia1; Mondini, Patrizia1; Manoukian, Siranoush5; Behar, Raquel2; Garcia, Encarna B. Gomez6,7; Meindl, Alfons8; Montagna, Marco9; Niederacher, Dieter10; Schmidt, Ane Y.11; Varesco, Liliana12; Wappenschmidt, Barbara13,14; Bolla, Manjeet K.15; Dennis, Joe15; Michailidou, Kyriaki15,16; Wang, Qin15; Aittomäki, Kristiina17; Andrulis, Irene L.18,19; Anton-Culver, Hoda20; Arndt, Volker21; Beckmann, Matthias W.22; Beeghly-Fadel, Alicia23; Benitez, Javier24,25; Boeckx, Bram26,27; Bogdanova, Natalia V.28,29,30; Bojesen, Stig E.31,32,33; Bonanni, Bernardo34; Brauch, Hiltrud35,36,37; Brenner, Hermann21,37,38,39; Burwinkel, Barbara40,41; Chang-Claude, Jenny42,43; Conroy, Don M.44; Couch, Fergus J.45; Cox, Angela46; Cross, Simon S.47; Czene, Kamila48; Devilee, Peter49,50; Dork, Thilo29; Eriksson, Mikael48; Fasching, Peter A.22,51; Figueroa, Jonine52,53; Fletcher, Olivia54; Flyger, Henrik55; Gabrielson, Marike48; Garcia-Closas, Montserrat53; Giles, Graham G.56,57; Gonzalez-Neira, Anna24; Guenel, Pascal58; Haiman, Christopher A.59; Hall, Per48; Hamann, Ute60; Hartman, Mikael61,62; Hauke, Jan13,14,63; Hollestelle, Antoinette64; Hopper, John L.57; Jakubowska, Anna65; Jung, Audrey42; Kosma, Veli-Matti66,67,68; Lambrechts, Diether26,27; Le Marchand, Loid69; Lindblom, Annika70; Lubinski, Jan65; Mannermaa, Arto66,67,68; Margolin, Sara71; Miao, Hui61; Milne, Roger L.56,57; Neuhausen, Susan L.72; Nevanlinna, Heli73; Olson, Janet E.74; Peterlongo, Paolo75; Peto, Julian76; Pylkäs, Katri77,78; Sawyer, Elinor J.79; Schmidt, Marjanka K.80,81; Schmutzler, Rita K.13,14,63; Schneeweiss, Andreas40,82; Schoemaker, Minouk J.83; See, Mee Hoong84; Southey, Melissa C.85; Swerdlow, Anthony83,86; Teo, Soo H.84,87; Toland, Amanda E.88; Tomlinson, Ian89,90; Truong, Therese58; van Asperen, Christi J.91; van den Ouweland, Ans M. W.92; van der Kolk, Lizet E.93; Winqvist, Robert77,78; Yannoukakos, Drakoulis94; Zheng, Wei23; Dunning, Alison M.44; Easton, Douglas F.15,44; Henderson, Alex95; Hogervorst, Frans B. L.93; Izatt, Louise96; Offitt, Kenneth97; Side, Lucy E.98; van Rensburg, Elizabeth J.99; McGuffog, Lesley15; Antoniou, Antonis C.15; Chenevix-Trench, Georgia4; Spurdle, Amanda B.4; Goldgar, David E.3; de la Hoya, Miguel2; Radice, Paolo1
Organizations: 1Fdn IRCCS Ist Ricovero & Cura Carattere Sci Ist N, Dept Res, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy.
2Hosp Clin San Carlos, IdISSC Inst Invest Sanitaria, Mol Oncol Lab CIBERONC, Madrid, Spain.
3Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA.
4QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld 4006, Australia.
5Fdn IRCCS Ist Ricovero & Cura Carattere Sci Ist N, Dept Med Oncol & Hematol, Unit Med Genet, Milan, Italy.
6MUMC, Sch Oncol & Dev Biol, Dept Clin Genet, Maastricht, Netherlands.
7MUMC, Sch Oncol & Dev Biol, GROW, Maastricht, Netherlands.
8Ludwig Maximilians Univ Munchen, Dept Obstet & Gynecol, Univ Hosp, Munich, Germany.
9Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy.
10Heinrich Heine Univ, Univ Hosp Dusseldorf, Dept Gynaecol & Obstet, Dusseldorf, Germany.
11Univ Copenhagen, Rigshosp, Ctr Genom Med, Copenhagen, Denmark.
12IRCCS AOU San Martino IST, Hereditary Canc Unit, Genoa, Italy.
13Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany.
14Univ Hosp Cologne, Fac Med, CIO, Cologne, Germany.
15Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.
16Cyprus Inst Neurol & Genet, Dept Electron Microscopy Mol Pathol, Nicosia, Cyprus.
17Univ Helsinki, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland.
18Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON, Canada.
19Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
20Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA.
21German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
22Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Obstet, Erlangen, Germany.
23Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Sch Med, Nashville, TN 37212 USA.
24Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain.
25Ctr Invest Red Enfermedades Raras CIBERER, Valencia, Spain.
26VIB, VIB Ctr Canc Biol, Leuven, Belgium.
27Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium.
28Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany.
29Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
30NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS.
31Copenhagen Univ Hosp, Herlevand Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark.
32Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark.
33Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
34Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy.
35Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.
36Univ Tubingen, Tubingen, Germany.
37German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany.
38German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.
39Natl Ctr Tumor Dis NCT, Heidelberg, Germany.
40Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany.
41German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany.
42German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.
43Univ Med Ctr Hamburg Eppendorf, UCCH, Res Grp Genet Canc Epidemiol, Hamburg, Germany.
44Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England.
45Mayo Clin, Dept Lab Med & Pathol, Rochester, NY USA.
46Univ Sheffield, Dept Oncol & Metab, Sheffield Inst Nucle Acids SInFoNiA, Sheffield, S Yorkshire, England.
47Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England.
48Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
49Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands.
50Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands.
51Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA.
52Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.
53NCI, Div Canc Epidemiol & Genet, Rockville, MD USA.
54Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England.
55Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark.
56Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
57Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia.
58Univ Paris Saclay, Univ Paris Sud, Ctr Res Epidemiol & Populat Hlth CESP, Canc & Environm Grp,INSERM, Villejuif, France.
59Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.
60Deutsch Krebsforschungszentrum DKFZ, Mol Genet Breast Canc, Heidelberg, Germany.
61Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.
62Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore.
63Univ Cologne, CMMC, Cologne, Germany.
64Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands.
65Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland.
66Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland.
67Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.
68Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland.
69Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96822 USA.
70Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
71Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
72City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, Duarte, CA USA.
73Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland.
74Mayo Clin, Dept Hlth Sci Res, Rochester, NY USA.
75Inst Mol Oncol, FIRC Italian Fdn Canc Res, IFOM, Milan, Italy.
76London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England.
77Univ Oulu, Bioctr Oulu, Lab Canc Genet & Tumor Biol, Canc & Translat Med Res Unit, Oulu, Finland.
78Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland.
79Kings Coll London, Guys Hosp, Res Oncol, London, England.
80Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands.
81Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands.
82Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany.
83Inst Canc Res, Div Genet & Epidemiol, London, England.
84Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia.
85Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia.
86Inst Canc Res, Div Breast Canc Res, London, England.
87Canc Res Malaysia, Subang Jaya, Selangor, Malaysia.
88Ohio State Univ, Comprehens Canc Ctr, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA.
89Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
90Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England.
91Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands.
92Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands.
93Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands.
94Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens, Greece.
95Newcastle Upon Tyne Hosp NHS Trust, Inst Genet Med, Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England.
96Guys & St Thomas NHS Fdn Trust, Clin Genet, London, England.
97Mem Sloan Kettering Canc Ctr, Dept Med Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA.
98Princess Anne Hosp, Wessex Clin Genet Serv, Mailpoint 627,Coxford Rd, Southampton SO16 5YA, Hants, England.
99Univ Pretoria, Dept Genet, Canc Genet Lab, Pretoria, South Africa.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2018111948390
Language: English
Published: John Wiley & Sons, 2018
Publish Date: 2018-11-19
Description:

Abstract

Although the spliceogenic nature of the BRCA2 c.68‐7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real‐time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case‐control analysis in 83,636 individuals. Co‐occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5‐fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68‐7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10⁻¹¹⁵. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86–1.24) nor for a deleterious effect of the variant when co‐occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68‐7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

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Series: Human mutation
ISSN: 1059-7794
ISSN-E: 1098-1004
ISSN-L: 1059-7794
Volume: 39
Issue: 5
Pages: 729 - 741
DOI: 10.1002/humu.23411
OADOI: https://oadoi.org/10.1002/humu.23411
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 Internal medicine
Subjects:
Funding: Funding information: the NHMRC Senior Research Fellowship Scheme; Spanish Instituto de Salud Carlos III funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds; Associazione Italiana per la Ricerca sul Cancro, Grant/Award Number: N◦15547 to P.R.; the Cancer Council Queensland; NHMRC Project grant scheme.
Copyright information: © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
  https://creativecommons.org/licenses/by/4.0/