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Patients With an Unclassified Genetic Variant in the BRCA1 or BRCA2 Genes Show Different Clinical Features From Those With a Mutation

From the Department of Clinical Genetics, University Hospital and Research Institute Growth & Development, and Department of Methodology and Statistics, the University of Maastricht, Maastricht, the Netherlands

Address reprint requests to Encarna B. Gómez-García, MD, PhD, Department of Clinical Genetics, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands; e-mail: Encarna.Gomezgarcia{at}gen.unimaas.nl

PURPOSE: To obtain and compare the probabilities of finding a mutation in the BRCA1 or BRCA2 genes, the clinical features, and the family history among patients with an unclassified variant (UV) and those with a pathogenic mutation.

PATIENTS AND METHODS: The study included 70 patients: 24 with a UV (BRCA1, n = 4; BRCA2, n = 19; both, n = 1), and 46 with a mutation (BRCA1, n = 32; BRCA2, n = 14). Two of the UVs were novel variants; the rest had been reported previously as UVs. Probabilities of finding a mutation were retrospectively obtained using BRCAPRO and Myriad II programs.

RESULTS: The probability to detect a mutation was significantly lower in the group of patients with a UV than in those with a mutation (BRCAPRO [mean ± standard deviation], 0.297 ± 0.312 v 0.627 ± 0.315, P = .001; and Myriad II, 0.124 ± 0.090 v 0.283 ± 0.176, P = .001, respectively). Independent predictive factors of finding either a UV or a mutation were number of affected relatives (2.9 ± 1.4 v 4.0 ± 1.9; P = .039) and number of tumors among relatives (3.3 ± 1.4 v 4.4 ± 1.8; P = .031), respectively.

CONCLUSION: The combined data about the predictive models show significant differences between both groups. Individual probabilities can be regarded as a help to guide the clinical management of patients with a UV in those genes. However, a definitive conclusion about the pathogenicity of a UV can not be obtained from the clinical features alone, but only in combination with biochemical and epidemiologic data.

Presented as an abstract at the Family Cancer Meeting, June 5-7, 2003, International Union Against Cancer (UICC), Oklahoma City, OK, and at the Familial Cancer Meeting, May 6-7, 2004, the European School of Oncology, Madrid, Spain.

Authors' disclosures of potential conflicts of interest are found at the end of this article.