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
Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Australia.
Breast Cancer Res. 2004;6(4):R401-7. doi: 10.1186/bcr806. Epub 2004 Jun 2.
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.
BRCA1和BRCA2基因的种系突变仅占遗传性乳腺癌的一部分，这表明还有其他基因与遗传性乳腺癌有关。最近，澳大利亚一个多病例乳腺癌家系队列研究（凯瑟琳·坎宁安家族性乳腺癌研究基金会联盟）报告称，共济失调毛细血管扩张症突变（ATM）基因中的一个杂合变体IVS10-6T→G会带来较高的乳腺癌风险。尽管该变体可导致截短的ATM产物，但其作为高 penetrance乳腺癌等位基因的临床意义或作为低 penetrance风险修饰因子的作用仍存在争议。
我们在澳大利亚四家主要的家族性癌症诊所，对一组接受BRCA1和BRCA2基因检测的乳腺癌和/或卵巢癌患者中ATM IVS10-6T→G变体的频率进行了测定。
495例患者中有7例（1.4%）为IVS10-6T→G变体的杂合子；据报道，在无乳腺癌家族史的未选择澳大利亚女性中，携带者率为725例中的6例（0.83%）（P = 0.4）。7名先证者中有2名还携带致病性BRCA1突变，1名患者有意义不确定的BRCA1未分类变体。
这些发现表明，ATM IVS10-6T→G变体在高危家族的患病个体中出现的频率似乎并不比普通人群显著更高。该变体作为低 penetrance等位基因或与其他基因（如BRCA1）相关的修饰基因的作用仍有可能。在对高危家族的患病个体进行突变筛查时，不建议对ATM IVS10-6T→G进行常规检测。
