Familial Cancer

, Volume 5, Issue 4, pp 379–387 | Cite as

BRCA1 and BRCA2 germline mutational spectrum and evidence for genetic anticipation in Portuguese breast/ovarian cancer families

  • Ana Peixoto
  • Natália Salgueiro
  • Catarina Santos
  • Graça Varzim
  • Patrícia Rocha
  • Maria José Soares
  • Deolinda Pereira
  • Helena Rodrigues
  • Maria José Bento
  • António Fráguas
  • Graça Moura
  • Fernando Regateiro
  • Sérgio Castedo
  • Manuel R. Teixeira
Editorial Notes


We present the first characterisation of the mutational spectrum of the entire coding sequences and exon–intron boundaries of the BRCA1 and BRCA2 genes as well as large BRCA1 rearrangements in Portuguese families with inherited predisposition to breast/ovarian cancer. Of the 100 probands studied, pathogenic mutations were identified in 22 (24.7%) of 89 breast and/or ovarian cancer families with more than one affected member (15 in BRCA1 and seven in BRCA2), but in none of the 11 patients without family history of cancer. One (6.7%) of the BRCA1 mutations is a large deletion involving exons 11–15. Seven pathogenic point mutations are novel: 2088C>T, 2156delinsCC, and 4255_4256delCT in BRCA1 and 4608_4609delTT, 5036delA, 5583_5584insT, and 8923C>T in BRCA2. The novel 2156delinsCC was identified in three probands from different families and probably represents a founder mutation in our population. We also found a previously reported 3450_3453del4 mutation in three unrelated patients. In addition to the 22 pathogenic mutations, we identified 19 missense mutations of uncertain pathogenic significance, three of them (5241G>C in BRCA1 and IVS6+13C>T and 3731T>C in BRCA2) previously undescribed. The percentage of cases with truncating mutations in BRCA1 and BRCA2 was higher in breast/ovarian cancer (37.0%, mostly BRCA1) and male breast cancer (40%, all BRCA2) families than in families with only female breast cancer (17.5%). Interestingly, we found evidence for genetic anticipation regarding age at diagnosis of both breast and ovarian cancer in those families presenting affected members in more than one generation. These findings should be taken into consideration while planning screening and prophylactic measures in families with inherited predisposition to breast and ovarian cancer.


BRCA1 BRCA2 Breast/ovarian cancer families Genetic anticipation Germline mutations 



The breast cancer information core


Denaturing gradient gel electrophoresis


Multiplex ligation-dependent probe amplification


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  1. 1.
    Newman B, Austin MA, Lee M et al (1988) Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci USA 85:3044–3048CrossRefPubMedGoogle Scholar
  2. 2.
    King MC, Marks JH, Mandell JB for The New York Breast Cancer Study Group (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646Google Scholar
  3. 3.
    Hendrickson BC, Judkins T, Ward BD et al (2005) Prevalence of five previously reported and recurrent BRCA1 genetic rearrangement mutations in 20,000 patients from hereditary breast/ovarian cancer families. Genes Chromosomes Cancer 43:309–313CrossRefPubMedGoogle Scholar
  4. 4.
    Mazoyer S (2005) Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat 25:415–422CrossRefPubMedGoogle Scholar
  5. 5.
    Simard J, Tonin P, Durocher F, et al (1994) Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet 8:392–398CrossRefPubMedGoogle Scholar
  6. 6.
    Thorlacius S, Olafsdottir G, Tryggvadottir L et al (1996) A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13:117–119CrossRefPubMedGoogle Scholar
  7. 7.
    Peelen T, van Vliet M, Petrij-Bosch A et al (1997) A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet 60:1041–1049PubMedGoogle Scholar
  8. 8.
    Díez O, Osorio A, Duran M et al (2003) Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat 22:301–312CrossRefPubMedGoogle Scholar
  9. 9.
    Soares R, Amendoeira I, Monteiro P et al (2000) Análise de mutações no gene BRCA1 em doentes com cancro da mama e/ou ovário em Portugal. Acta Med Port 13:313–321Google Scholar
  10. 10.
    Duarte F, Cameselle-Teijeiro JF, Soares R et al (2002) Análisis de mutaciones en los genes BRCA1 y BRCA2 en pacientes com cáncer de mama y ovario del norte de Portugal y Galicia. Rev Clin Esp 202:259–263PubMedGoogle Scholar
  11. 11.
    Parmigiani G, Berry D, Aguilar O (1998) Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62:145–158CrossRefPubMedGoogle Scholar
  12. 12.
    Berry DA, Iversen ES Jr, Gudbjartsson DF et al (2002) BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20:2701–2712CrossRefPubMedGoogle Scholar
  13. 13.
    Van der Hout AH, Van den Ouweland MW, Van der Luijt RB et al (2006, in press) A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2. Application in a Dutch cancer clinic setting. Hum MutatGoogle Scholar
  14. 14.
    Sanger F, Nicklen S, Coulson AR (1997) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467CrossRefGoogle Scholar
  15. 15.
    Euhus DM, Smith KC, Robinson L et al (2002) Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst 94:844–851PubMedGoogle Scholar
  16. 16.
    Shih HA, Couch FJ, Nathanson KL et al (2002) BRCA1 and BRCA2 mutation frequency in women evaluated in a breast cancer risk evaluation clinic. J Clin Oncol 20:994–999CrossRefPubMedGoogle Scholar
  17. 17.
    Claes K, Poppe B, Coene I et al (2004) BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer 90:1244–1251CrossRefPubMedGoogle Scholar
  18. 18.
    Neuhausen S, Gilewski T, Norton L et al (1996) Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 13:126–128CrossRefPubMedGoogle Scholar
  19. 19.
    Petrij-Bosch A, Peelen T, van Vliet M et al (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17:341–345CrossRefPubMedGoogle Scholar
  20. 20.
    Møller P, Borg A, Heimdal K et al (2001) The BRCA1 syndrome and other inherited breast or breast-ovarian cancers in a Norwegian prospective series. Eur J Cancer 37:1027–1032CrossRefPubMedGoogle Scholar
  21. 21.
    Vega A, Campos B, Bressac-De-Paillerets B et al (2001) The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum Mutat 17:520–521CrossRefPubMedGoogle Scholar
  22. 22.
    Montagna M, Dalla Palma M, Menin C et al (2003) Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet 12:1055–1061CrossRefPubMedGoogle Scholar
  23. 23.
    Gad S, Caux-Moncoutier V, Pages-Berhouet S et al (2002) Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families. Oncogene 21:6841–6847CrossRefPubMedGoogle Scholar
  24. 24.
    Osorio A, de la Hoya M, Rodriguez-Lopez R et al (2002) Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer. Int J Cancer 99:305–309CrossRefPubMedGoogle Scholar
  25. 25.
    Vallon-Christersson J, Cayanan C, Haraldsson K et al (2001) Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families. Hum Mol Genet 10:353–360CrossRefPubMedGoogle Scholar
  26. 26.
    Szabo CI, Wagner LA, Francisco LV et al (1996) Human, canine and murine BRCA1 genes: sequence comparison among species. Hum Mol Genet 5:1289–1298CrossRefPubMedGoogle Scholar
  27. 27.
    Westphalen AA, Russell AM, Buser M et al (2005) Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer. Hum Genet 116:461–465CrossRefPubMedGoogle Scholar
  28. 28.
    Horwitz M (1997) The genetics of familial leukemia. Leukemia 11:1347–1359CrossRefPubMedGoogle Scholar
  29. 29.
    Segel GB, Lichtman MA (2004) Familial (inherited) leukemia, lymphoma, and myeloma: an overview. Blood Cells Mol Dis 32:246–261CrossRefPubMedGoogle Scholar
  30. 30.
    Dagan E, Gershoni-Baruch R (2002) Anticipation in hereditary breast cancer. Clin Genet 62:147–150CrossRefPubMedGoogle Scholar
  31. 31.
    Paterson AD, Kennedy JL, Petronis A (1996) Evidence for genetic anticipation in non-Mendelian diseases. Am J Hum Genet 59:264–268PubMedGoogle Scholar
  32. 32.
    Hoh J, Heitjan DF, Merette C et al (2001) Ascertainment and anticipation in family studies. Hum Hered 51:23–26CrossRefPubMedGoogle Scholar
  33. 33.
    Goldberg JM, Piver MS, Jishi MF et al (1997) Age at onset of ovarian cancer in women with a strong family history of ovarian cancer. Gynecol Oncol 66:3–9CrossRefPubMedGoogle Scholar
  34. 34.
    Tryggvadottir L, Sigvaldason H, Olafsdottir GH et al (2006) Population-based study of changing breast cancer risk in Iceland BRCA2 mutation carriers, 1920–2000. J Natl Cancer Inst 98:116–122PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Ana Peixoto
    • 1
  • Natália Salgueiro
    • 1
  • Catarina Santos
    • 1
  • Graça Varzim
    • 1
  • Patrícia Rocha
    • 1
  • Maria José Soares
    • 1
  • Deolinda Pereira
    • 2
  • Helena Rodrigues
    • 2
  • Maria José Bento
    • 3
  • António Fráguas
    • 4
  • Graça Moura
    • 5
  • Fernando Regateiro
    • 6
  • Sérgio Castedo
    • 1
  • Manuel R. Teixeira
    • 1
  1. 1.Department of GeneticsPortuguese Oncology InstitutePortoPortugal
  2. 2.Departments of OncologyPortuguese Oncology InstitutePortoPortugal
  3. 3.Departments of EpidemiologyPortuguese Oncology InstitutePortoPortugal
  4. 4.Espírito Santo HospitalÉvoraPortugal
  5. 5.St. António General HospitalPortoPortugal
  6. 6.Coimbra University HospitalCoimbraPortugal

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