Twenty-three novel BRCA1 and BRCA2 sequence variations identified in a cohort of Swiss breast and ovarian cancer families

BRCA1 and BRCA2 are the major genes predisposing to breast–ovarian cancer (i.e., breast or ovarian cancer or both). Since 1994, hundreds of distinct germline alterations have been reported in these two genes. Besides pathogenic mutations resulting in loss of function of the protein, an increased num...

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Published in:Cancer genetics and cytogenetics 2006-08, Vol.169 (1), p.62-68
Main Authors: Maillet, Philippe, Chappuis, Pierre Olivier, Khoshbeen-Boudal, Mary, Sciretta, Véronique, Sappino, André-Pascal
Format: Article
Language:English
Subjects:
Adult
Breast Neoplasms - genetics
Cohort Studies
Female
Genes, BRCA1
Genes, BRCA2
Humans
Middle Aged
Mutation, Missense
Ovarian Neoplasms - genetics
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Summary:BRCA1 and BRCA2 are the major genes predisposing to breast–ovarian cancer (i.e., breast or ovarian cancer or both). Since 1994, hundreds of distinct germline alterations have been reported in these two genes. Besides pathogenic mutations resulting in loss of function of the protein, an increased number of variants of unknown clinical significance have been described. In a cohort of 350 Swiss breast–ovarian cancer families, the systematic search for BRCA1/ BRCA2 germline mutations was carried out using denaturating high-performance liquid chromatography as the first screening procedure. The screening strategy resulted in the identification of 23 alterations not previously reported: 9 in BRCA1 and 14 in BRCA2. By using the available tools to assign a functional role to newly identified sequence variations, 5 (22%) of these were classified as new disease-causing mutations, 5 (22%) were classified as benign polymorphisms, and the remaining 13 (56%) alterations were considered as unclassified variants. These data illustrate the major challenge for clinical oncologists currently facing the interpretation of alterations identified in BRCA1 or BRCA2. The key points are to classify these genetic variations as pathogenic mutations, benign polymorphisms, or variants of unknown clinical significance and to adequately use this information for the management of high-risk individuals and their families.
ISSN:0165-4608
1873-4456
DOI:10.1016/j.cancergencyto.2006.03.010