Breast Cancer Research and Treatment

, Volume 110, Issue 2, pp 377–385 | Cite as

G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history

  • Theodore Anagnostopoulos
  • Maroulio Pertesi
  • Irene Konstantopoulou
  • Sofia Armaou
  • Smaragda Kamakari
  • George Nasioulas
  • Athanassios Athanasiou
  • Alex Dobrovic
  • Mary-Anne Young
  • David Goldgar
  • George Fountzilas
  • Drakoulis Yannoukakos


We have performed screening in 287 breast/ovarian cancer families in Greece which has revealed that ∼12% (8/65) of all index patients-carriers of a deleterious mutation in BRCA1 and BRCA2 genes, contain the base substitution G to A at position 5331 of BRCA1 gene. This generates the amino acid change G1738R for which based on a combination of genetic, in silico and histopathological analysis there are strong suggestions that it is a causative mutation. In this paper, we present further evidence suggesting the pathogenicity of this variant. Forty breast/ovarian cancer patients were reported in 11 Greek families: the above eight living in Greece, two living in Australia and one in USA, all containing G1738R. Twenty of these patients were screened and were all found to be carriers of the same base substitution. In addition, we have detected the same base change in five breast/ovarian cancer patients after screening 475 unselected patient samples with no apparent family history. The mean age of onset for all the above patients was 39.4 and 53.6 years for breast and ovarian cancer cases, respectively. A multi-factorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 developed previously was applied on G1738R and the odds of it being a deleterious mutation was estimated to be 11470:1. In order to explain the prevalence of this mutation mainly in the Greek population, its genealogical history was examined. DNA samples were collected from 11 carrier families living in Greece, Australia and USA. Screening of eight intragenic SNPs, three intragenic and seven extragenic microsatellite markers and comparison with control individuals, suggested a common origin for the mutation while the time to its most recent common ancestor was estimated to be 11 generations (about 275 years assuming a generational interval of 25 years) with a 1-lod support interval of 4–24 generations (100–600 years). Considering the large degree of genetic heterogeneity in the Greek population, the identification of a frequent founder mutation greatly facilitates genetic screening.


BRCA1 Genetic screening Founder mutation G1738R 



We are indebted to the patients for their collaboration in this study. This work was partly supported by the Hellenic Cooperative Oncology Group (HeCOG), the Greek Ministry of Health and Welfare (MOHAW), the Hellenic Institute for Occupational Health and Safety, the IST-2004-NEMOSLAB 027804 program and the Greek General Secretary for Research and Technology (GSRT) Program, Research in Excellence II and 05NONEU21, funded by 75% from the European Union.


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Theodore Anagnostopoulos
    • 1
  • Maroulio Pertesi
    • 1
  • Irene Konstantopoulou
    • 1
    • 2
  • Sofia Armaou
    • 1
  • Smaragda Kamakari
    • 2
  • George Nasioulas
    • 3
  • Athanassios Athanasiou
    • 4
  • Alex Dobrovic
    • 5
  • Mary-Anne Young
    • 5
  • David Goldgar
    • 6
  • George Fountzilas
    • 7
    • 8
  • Drakoulis Yannoukakos
    • 1
  1. 1.Molecular Diagnostics LaboratoryIRRP, National Centre for Scientific Research “Demokritos”Aghia Paraskevi, AthensGreece
  2. 2.BioGenomicaCentre for Genetic Research and AnalysisAthensGreece
  3. 3.Molecular Biology Research Center HYGEIA «Antonis Papayiannis», DTCA HYGEIAMaroussi, AthensGreece
  4. 4.Department of Medical Oncology-AMetaxa Cancer HospitalPiraeusGreece
  5. 5.Familial Cancer CentrePeter MacCallum InstituteMelbourneAustralia
  6. 6.Department of DermatologyUniversity of UtahSalt Lake CityUSA
  7. 7.Department of Medical Oncology, “Papageorgiou” HospitalAristotle University of Thessaloniki School of MedicineThessalonikiGreece
  8. 8.Hellenic Cooperative Oncology GroupAthensGreece

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