Frequency of the ATMIVS10-6T→G variant in Australian multiple-case breast cancer families

Autor: Lindeman, Geoffrey J, Hiew, Melody, Visvader, Jane E, Leary, Jennifer, Field, Michael, Gaff, Clara L, Gardner, RJ McKinlay, Trainor, Kevin, Cheetham, Glenice, Suthers, Graeme, Kirk, Judy
Zdroj: Breast Cancer Research; August 2004, Vol. 6 Issue: 4
Abstrakt: Background: Germline mutations in the genes BRCA1and BRCA2account for only a proportion of hereditary breast cancer, suggesting that additional genes contribute to hereditary breast cancer. Recently a heterozygous variant in the ataxia–telangiectasia mutated (ATM) gene, IVS10-6T→G, was reported by an Australian multiple-case breast cancer family cohort study (the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer) to confer a substantial breast cancer risk. Although this variant can result in a truncated ATM product, its clinical significance as a high-penetrance breast cancer allele or its role as a low-penetrance risk-modifier is controversial. Methods: We determined the frequency of ATMIVS10-6T→G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1and BRCA2genetic testing at four major Australian familial cancer clinics. Results: Seven of 495 patients (1.4%) were heterozygous for the IVS10-6T→G variant; the carrier rate in unselected Australian women with no family history of breast cancer is reported to be 6 of 725 (0.83%) (P= 0.4). Two of the seven probands also harboured a pathogenic BRCA1mutation and one patient had a BRCA1unclassified variant of uncertain significance. Conclusion: These findings indicate that the ATMIVS10-6T→G variant does not seem to occur at a significantly higher frequency in affected individuals from high-risk families than in the general population. A role for this variant as a low-penetrance allele or as a modifying gene in association with other genes (such as BRCA1) remains possible. Routine testing for ATMIVS10-6T→G is not warranted in mutation screening of affected individuals from high-risk families.
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