Frequency of the ATM IVS10-6T-->G variant in Australian multiple-case breast cancer families

• Published in: Breast cancer research : BCR 2004-01, Vol.6 (4), p.R401-R407, Article R401
• Main Authors: Lindeman, Geoffrey J, Hiew, Melody, Visvader, Jane E, Leary, Jennifer, Field, Michael, Gaff, Clara L, Gardner, R J McKinlay, Trainor, Kevin, Cheetham, Glenice, Suthers, Graeme, Kirk, Judy
• Format: Article
• Language: English
• Subjects: Adult; Aged; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia Mutated Proteins; Australia - epidemiology; Australians; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms, Male - genetics; Cancer; Cell Cycle Proteins; DNA-Binding Proteins; Family; Female; Gene Frequency - genetics; Gene mutations; Genes, BRCA1; Genes, BRCA2; Genetic aspects; Genetic Carrier Screening; Genetic screening; Genetic Testing; Germ-Line Mutation - genetics; Health aspects; Humans; Introns - genetics; Male; Middle Aged; Oncology, Experimental; Ovarian cancer; Ovarian Neoplasms - genetics; Protein-Serine-Threonine Kinases - genetics; Retrospective Studies; Tumor Suppressor Proteins
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/bcr806

Germline mutations in the genes BRCA1 and BRCA2 account 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. We determined the frequency of ATM IVS10-6T-->G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1 and BRCA2 genetic testing at four major Australian familial cancer clinics. 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 BRCA1 mutation and one patient had a BRCA1 unclassified variant of uncertain significance. These findings indicate that the ATM IVS10-6T-->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 ATM IVS10-6T-->G is not warranted in mutation screening of affected individuals from high-risk families.