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This article is part of the supplement: The Third International Symposium on the Molecular Biology of Breast Cancer

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The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk

B Frank1, K Hemminki12, M Wirtenberger1, JL Bermejo1, P Bugert3, R Klaes4, RK Schmutzler5, B Wappenschmidt5, CR Bartram4 and B Burwinkel1

Author Affiliations

1 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany

2 Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden

3 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden–Württemberg–Hessia, University of Heidelberg, Faculty of Clinical Medicine, Mannheim, Germany

4 Institute of Human Genetics, University of Heidelberg, Germany

5 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Germany

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Breast Cancer Research 2005, 7(Suppl 2):P1.18  doi:10.1186/bcr1105

The electronic version of this article is the complete one and can be found online at:

Published:17 June 2005



Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20–30% of breast cancers involving ligand-independent activation and more aggressive growth behaviour, reduced response to chemotherapy and hormonal therapy, as well as poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis.


The ERBB2 variants Ile654Val, Ile655Val and Ala1170Pro were investigated for their influence on familial breast cancer risk by sequencing and TaqMan allelic discrimination.


The case–control study analysing 348 German familial breast cancer cases and 960 controls showed no significant association of Ile655Val and Ala1170Pro with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could not be detected either. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (odds ratio = 2.56, 95% confidence interval = 1.08-6.08, P = 0.028).


The rare Val654 is linked to the more frequent Val655, resulting in two consecutive valine residues instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654–Val655 allele provokes receptor dimerisation and activation, thus stimulating kinase activity and cell transformation. We hypothesise that ERBB2 Val654 represents an oncogenic variant that might, in addition, influence clinical outcome and predict worse prognosis. The occurrence of the Val654–Val655 haplotype in human breast cancer cells (MCF-7) supports the significance of our results.


This manuscript has been accepted for publication [1].


  1. Frank B, et al.: The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk.

    Carcinogenesis 2005, 26:643-647. PubMed Abstract | Publisher Full Text OpenURL