Both breast and ovarian cancers are associated with HER2 receptor activation, which usually results from receptor overexpression and/or gene amplification. The HER-2 gene harbors a polymorphism at codon 655 (GTC/valine to ATC/isoleucine) in the transmembrane domain region, which has been associated with an elevated risk of breast cancer. The objective of this study was to determine whether the polymorphism is under a selection pressure during breast and ovarian carcinogenesis. The Ile/Val genotype was present in 41% (9/22) of the normal DNA of breast cancer patients. An allelic imbalance in the tumor tissue was found in three breast tumors, with overrepresentation of the Val allele. HER-2 was amplified and overexpressed in these tumors. Half of the eight ovarian tumor patients carried heterozygous Ile/Val genotypes. In contrast to breast tumors, all these ovarian cancer specimens showed the presence of the Ile allele. In our selected set of tumors, the Val allele was overrepresented in the subset of HER2-positive breast cancers and the Ile allele in serous ovarian cancer. Further analyses of tumors with known gene amplifications and overexpression may reveal novel associations between germline polymorphisms and development of sporadic tumors.