Breast Cancer Research and Treatment

, Volume 131, Issue 1, pp 333–340 | Cite as

The BRCA2 c.9004G>A (E2003K) variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent

  • Stephanie Cote
  • Suzanna L. Arcand
  • Robert Royer
  • Serge Nolet
  • Anne-Marie Mes-Masson
  • Parviz Ghadirian
  • William D. Foulkes
  • Marc Tischkowitz
  • Steven A. Narod
  • Diane Provencher
  • Patricia N. Tonin
Brief Report


Specific BRCA1 and BRCA2 mutations recur in French Canadian breast and/or ovarian cancer families because of common ancestors, facilitating carrier detection in this population. We recently reported a BRCA2 c.9004G>A variant of unknown clinical significance in two French Canadian breast cancer families. It confers a E3002K alteration in the conserved C-terminus domain of BRCA2, and has been reported in non-French Canadian cancer families. Seven variant positive French Canadian families have since been identified by mutation screening of referrals to hereditary cancer clinics. In this article, we describe the cancer phenotypes of these families and further assess the contribution of this variant in the French Canadian population. We screened index breast cancer cases from 58 cancer families with at least three confirmed cases of breast and/or ovarian cancer and 960 breast cancer cases (48 years mean age) not selected for family history of cancer that were previously found not to carry the most common BRCA1 and BRCA2 mutations reported in this population. The index variant-positive cases from each family had breast cancer between the ages of 35–55 years (43 years mean age); and reported close relatives with breast cancer diagnoses between the ages of 28–84 years (57 years mean age). Three families had ovarian or peritoneal cancers. BRCA2-associated cancers, such as bladder, esophagus, pancreas, prostate, and thyroid cancers also occurred in these families. One c.9004G>A carrier also harbored the PALB2 c.2323C>T (Q775X) mutation found to recur in French Canadian breast cancer cases. No new BRCA2 variant carriers were identified in mutation screens. The absence of BRCA2 c.9004G>A carriers in the breast cancer cases not selected for family history contrasts with familial cases, supporting a pathogenic status for this variant and addition to the existing common BRCA1 and BRCA2 mutation-screening panel for French Canadian breast and/or ovarian cancer families.


BRCA2 E3002K Hereditary breast cancer Variants of unknown clinical significance Founder mutations French Canadians PALB2 


  1. 1.
    Narod SA, Foulkes WD (2004) BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4(9):665–676. doi:10.1038/nrc1431 PubMedCrossRefGoogle Scholar
  2. 2.
    Lee E, McKean-Cowdin R, Ma H, Chen Z, Van Den Berg D, Henderson BE, Bernstein L, Ursin G (2008) Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res 10(1):19. doi:10.1186/bcr1865 CrossRefGoogle Scholar
  3. 3.
    Domchek S, Weber BL (2008) Genetic variants of uncertain significance: flies in the ointment. J Clin Oncol 26(1):16–17. doi:10.1200/JCO.2007.14.4154 PubMedCrossRefGoogle Scholar
  4. 4.
    Cavallone L, Arcand SL, Maugard CM, Nolet S, Gaboury LA, Mes-Masson AM, Ghadirian P, Provencher D, Tonin PN (2010) Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer 9(4):507–517. doi:10.1007/s10689-010-9372-3 PubMedCrossRefGoogle Scholar
  5. 5.
    Holloman WK (2011) Unraveling the mechanism of BRCA2 in homologous recombination. Nat Struct Mol Biol 18(7):748–754. doi:10.1038/nsmb.2096 PubMedCrossRefGoogle Scholar
  6. 6.
    Szabo C, Masiello A, Ryan JF, Brody LC (2000) The breast cancer information core: database design, structure, and scope. Hum Mutat 16(2):123–131. doi:10.1002/1098-1004(200008)16:2<123:AID-HUMU4>3.0.CO;2-Y PubMedCrossRefGoogle Scholar
  7. 7.
    Salazar R, Cruz-Hernandez JJ, Sanchez-Valdivieso E, Rodriguez CA, Gomez-Bernal A, Barco E, Fonseca E, Portugal T, Gonzalez-Sarmiento R (2006) BRCA1–2 mutations in breast cancer: identification of nine new variants of BRCA1–2 genes in a population from central Western Spain. Cancer Lett 233(1):172–177. doi:10.1016/j.canlet.2005.03.006 PubMedCrossRefGoogle Scholar
  8. 8.
    Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT (2011) LOVD v.2.0: the next generation in gene variant databases. Hum Mutat 32(5):557–563. doi:10.1002/humu.21438 PubMedCrossRefGoogle Scholar
  9. 9.
    Tonin PN, Mes-Masson AM, Futreal PA, Morgan K, Mahon M, Foulkes WD, Cole DE, Provencher D, Ghadirian P, Narod SA (1998) Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet 63(5):1341–1351. doi:10.1086/302099 PubMedCrossRefGoogle Scholar
  10. 10.
    Oros KK, Ghadirian P, Greenwood CM, Perret C, Shen Z, Paredes Y, Arcand SL, Mes-Masson AM, Narod SA, Foulkes WD, Provencher D, Tonin PN (2004) Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5 BRCA1 and BRCA2 mutations. Int J Cancer 112(3):411–419. doi:10.1002/ijc.20406 PubMedCrossRefGoogle Scholar
  11. 11.
    Oros KK, Ghadirian P, Maugard CM, Perret C, Paredes Y, Mes-Masson AM, Foulkes WD, Provencher D, Tonin PN (2006) Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent. Clin Genet 70(4):320–329. doi:10.1111/j.1399-0004.2006.00673.x PubMedCrossRefGoogle Scholar
  12. 12.
    Oros KK, Leblanc G, Arcand SL, Shen Z, Perret C, Mes-Masson AM, Foulkes WD, Ghadirian P, Provencher D, Tonin PN (2006) Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families. BMC Med Genet 7:23. doi:10.1186/1471-2350-7-23 PubMedCrossRefGoogle Scholar
  13. 13.
    Manning AP, Abelovich D, Ghadirian P, Lambert JA, Frappier D, Provencher D, Robidoux A, Peretz T, Narod SA, Mes-Masson AM, Foulkes WD, Wang T, Morgan K, Fujiwara TM, Tonin PN (2001) Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families. Hum Hered 52(2):116–120PubMedCrossRefGoogle Scholar
  14. 14.
    Tonin PN (2006) The limited spectrum of pathogenic BRCA1 and BRCA2 mutations in the French Canadian breast and breast-ovarian cancer families, a founder population of Quebec, Canada. Bull Cancer 93(9):841–846PubMedGoogle Scholar
  15. 15.
    Scriver CR (2001) Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet 2:69–101. doi:10.1146/annurev.genom.2.1.69 PubMedCrossRefGoogle Scholar
  16. 16.
    Laberge AM, Michaud J, Richter A, Lemyre E, Lambert M, Brais B, Mitchell GA (2005) Population history and its impact on medical genetics in Quebec. Clin Genet 68(4):287–301. doi:10.1111/j.1399-0004.2005.00497.x PubMedCrossRefGoogle Scholar
  17. 17.
    Vezina H, Durocher F, Dumont M, Houde L, Szabo C, Tranchant M, Chiquette J, Plante M, Laframboise R, Lepine J, Nevanlinna H, Stoppa-Lyonnet D, Goldgar D, Bridge P, Simard J (2005) Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French–Canadian breast/ovarian cancer families. Hum Genet 117(2–3):119–132. doi:10.1007/s00439-005-1297-9 PubMedCrossRefGoogle Scholar
  18. 18.
    Simard J, Dumont M, Moisan AM, Gaborieau V, Malouin H, Durocher F, Chiquette J, Plante M, Avard D, Bessette P, Brousseau C, Dorval M, Godard B, Houde L, Joly Y, Lajoie MA, Leblanc G, Lepine J, Lesperance B, Vezina H, Parboosingh J, Pichette R, Provencher L, Rheaume J, Sinnett D, Samson C, Simard JC, Tranchant M, Voyer P, Easton D, Tavtigian SV, Knoppers BM, Laframboise R, Bridge P, Goldgar D (2007) Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French–Canadian families with high risk of breast and ovarian cancer. J Med Genet 44(2):107–121. doi:10.1136/jmg.2006.044388 PubMedCrossRefGoogle Scholar
  19. 19.
    Ghadirian P, Robidoux A, Zhang P, Royer R, Akbari M, Zhang S, Fafard E, Costa M, Martin G, Potvin C, Patocskai E, Larouche N, Younan R, Nassif E, Giroux S, Narod SA, Rousseau F, Foulkes WD (2009) The contribution of founder mutations to early-onset breast cancer in French–Canadian women. Clin Genet 76(5):421–426. doi:10.1111/j.1399-0004.2009.01277.x PubMedCrossRefGoogle Scholar
  20. 20.
    Arcand SL, Maugard CM, Ghadirian P, Robidoux A, Perret C, Zhang P, Fafard E, Mes-Masson AM, Foulkes WD, Provencher D, Narod SA, Tonin PN (2008) Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. Breast Cancer Res Treat 108(3):399–408. doi:10.1007/s10549-007-9608-6 PubMedCrossRefGoogle Scholar
  21. 21.
    Cancer risks in BRCA2 mutation carriers. The breast cancer linkage consortium (1999). J Natl Cancer Inst 91 (15):1310–1316Google Scholar
  22. 22.
    Foulkes WD, Ghadirian P, Akbari MR, Hamel N, Giroux S, Sabbaghian N, Darnel A, Royer R, Poll A, Fafard E, Robidoux A, Martin G, Bismar TA, Tischkowitz M, Rousseau F, Narod SA (2007) Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res 9(R6):83. doi:10.1186/bcr1828 CrossRefGoogle Scholar
  23. 23.
    Tischkowitz M, Xia B, Sabbaghian N, Reis-Filho JS, Hamel N, Li G, van Beers EH, Li L, Khalil T, Quenneville LA, Omeroglu A, Poll A, Lepage P, Wong N, Nederlof PM, Ashworth A, Tonin PN, Narod SA, Livingston DM, Foulkes WD (2007) Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA 104(16):6788–6793. doi:10.1073/pnas.0701724104 PubMedCrossRefGoogle Scholar
  24. 24.
    Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR (2009) Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 76(1):1–18. doi:10.1111/j.1399-0004.2009.01230.x PubMedCrossRefGoogle Scholar
  25. 25.
    Tonin PN, Maugard CM, Perret C, Mes-Masson AM, Provencher DM (2007) A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families. Fam Cancer 6(4):491–497. doi:10.1007/s10689-007-9152-x PubMedCrossRefGoogle Scholar
  26. 26.
    Tonin PN, Perret C, Lambert JA, Paradis AJ, Kantemiroff T, Benoit MH, Martin G, Foulkes WD, Ghadirian P (2001) Founder BRCA1 and BRCA2 mutations in early-onset French Canadian breast cancer cases unselected for family history. Int J Cancer 95(3):189–193PubMedCrossRefGoogle Scholar
  27. 27.
    Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, Zheng N, Chen PL, Lee WH, Pavletich NP (2002) BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297(5588):1837–1848. doi:10.1126/science.297.5588.1837 PubMedCrossRefGoogle Scholar
  28. 28.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921. doi:10.1038/nature03445 PubMedCrossRefGoogle Scholar
  29. 29.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917. doi:10.1038/nature03443 PubMedCrossRefGoogle Scholar
  30. 30.
    Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451(7182):1111–1115. doi:10.1038/nature06548 PubMedCrossRefGoogle Scholar
  31. 31.
    Karchin R, Agarwal M, Sali A, Couch F, Beattie MS (2008) Classifying variants of undetermined significance in BRCA2 with protein likelihood ratios. Cancer Inform 6:203–216PubMedGoogle Scholar
  32. 32.
    Thompson D, Easton D (2001) Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68(2):410–419. doi:10.1086/318181 PubMedCrossRefGoogle Scholar
  33. 33.
    Easton DF, Deffenbaugh AM, Pruss D, Frye C, Wenstrup RJ, Allen-Brady K, Tavtigian SV, Monteiro AN, Iversen ES, Couch FJ, Goldgar DE (2007) A systematic genetic assessment of 1, 433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet 81(5):873–883. doi:10.1086/521032 PubMedCrossRefGoogle Scholar
  34. 34.
    Tischkowitz M, Xia B (2010) PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res 70(19):7353–7359. doi:10.1158/0008-5472.CAN-10-1012 PubMedCrossRefGoogle Scholar
  35. 35.
    Wasielewski M, Out AA, Vermeulen J, Nielsen M, van den Ouweland A, Tops CM, Wijnen JT, Vasen HF, Weiss MM, Klijn JG, Devilee P, Hes FJ, Schutte M (2010) Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer. Breast Cancer Res Treat 124(3):635–641. doi:10.1007/s10549-010-0801-7 PubMedCrossRefGoogle Scholar
  36. 36.
    Kuznetsov SG, Liu P, Sharan SK (2008) Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med 14(8):875–881. doi:10.1038/nm.1719 PubMedCrossRefGoogle Scholar
  37. 37.
    Gagnon A, Heyer E (2001) Fragmentation of the Quebec population genetic pool (Canada): Evidence from the genetic contribution of founders per region in the 17th and 18th centuries. Am J Phys Anthropol 114(1):30–41PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Stephanie Cote
    • 1
    • 2
  • Suzanna L. Arcand
    • 3
  • Robert Royer
    • 4
  • Serge Nolet
    • 5
    • 6
  • Anne-Marie Mes-Masson
    • 7
    • 8
  • Parviz Ghadirian
    • 9
  • William D. Foulkes
    • 3
    • 10
    • 11
    • 12
    • 13
  • Marc Tischkowitz
    • 10
    • 11
  • Steven A. Narod
    • 4
  • Diane Provencher
    • 7
    • 14
  • Patricia N. Tonin
    • 3
    • 12
    • 13
    • 15
  1. 1.Service de Médecine Génique, Département de MédecineCentre Hospitalier de l’Université de MontréalMontrealCanada
  2. 2.Département des Sciences BiomédicalesUniversité de MontréalMontrealCanada
  3. 3.The Research Institute of the McGill University Health CentreMontrealCanada
  4. 4.Department of Public Health, Women’s College Research InstituteThe University of TorontoTorontoCanada
  5. 5.Département de PathologieCentre Hospitalier de l’Université de MontréalMontrealCanada
  6. 6.Département de Pathologie et Biologie CellulaireUniversité de MontréalMontrealCanada
  7. 7.Institut du cancer de MontréalCentre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)MontrealCanada
  8. 8.Département de MédecineUniversité de MontréalMontrealCanada
  9. 9.Epidemiology Research UnitCentre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)MontrealCanada
  10. 10.Program in Cancer Genetics, Departments of Oncology and Human GeneticsMcGill UniversityMontrealCanada
  11. 11.Lady Davis Institute, Segal Cancer CentreJewish General HospitalMontrealCanada
  12. 12.Department of MedicineMcGill UniversityMontrealCanada
  13. 13.Department of Human GeneticsMcGill UniversityMontrealCanada
  14. 14.Division of Gynecologic OncologyUniversité de MontréalMontrealCanada
  15. 15.Medical GeneticsMontrealCanada

Personalised recommendations