These are rare genes with a population frequency of <0.6%. The phenotypes associated with these mutations have not been clearly delineated and therefore, the clinical utility of these genotypes has yet to be established. Ataxia telangiectasia is an autosomal recessive condition due to homozygous mutations in ATM. Clinically this condition results in progressive cerebellar ataxia and oculomotor apraxia, conjunctival telangiectasia, immunodeficiency and increased risk of malignancy including BC. It had been suggested for several years that ATM heterozygotes have increased BC risk (38), although this has been controversial. However, recent studies (39) have confirmed an increased RR of BC of 2.23 (95% CI 1.16�C4.28) in ATM heterozygotes. This RR increases <50 years. Mutations described in ATM include truncating mutations, splice site and missense mutations. ATM is a protein <a href="http://www.selleckchem.com/products/Bafilomycin-A1.html
">Bafilomycin A1 chemical structure Phosphoprotein phosphatase
kinase involved in the response to double-stranded DNA breaks in a pathway that includes TP53, BRCA1 and CHEK2. It is difficult to assess the clinical utility of genetic testing for ATM at present. The penetrance of the gene is approximately 15% and estimating which mutation carriers will develop BC is not possible. However, these women may merit different approaches to treatment of BC due to the increased radiosensitivity associated with ATM mutations. The checkpoint kinase gene CHEK2 encodes a protein that is a signalling component in the cellular response to DNA damage. It is involved in the same pathway as TP53 and BRCA1. CHEK2 is a tumour suppressor gene and somatic mutations have been identified in a number of malignancies. A particular germline mutation 1100delC www.selleckchem.com/products/AP24534.html
has been shown to give an RR of BC of 2.34 (95% CI 1.72�C3.2) (40). It is present in 0.2�C1% of European populations and 4.2% of BC families, although the mutation frequency varies between populations. A number of other CHEK2 mutations have been reported in BC families, but the clinical significance of these is unclear. Carriers of 1100delC mutation have an increased risk of bilateral BC. Originally it was suggested that it may also contribute to male BC, but this has not been verified. There does not appear to be an increased risk of other malignancies with heterozygous CHEK2 mutations. A recent publication (41) has described families with homozygous CHEK2* 1100delC mutations. Women homozygous for the mutation have a much higher risk of BC �C estimated to be sixfold. There also appears to be an increased risk of other malignancies within these families including colorectal cancer, although clearly further work needs to be undertaken. BRIP1 encodes for a protein that was identified as a binding partner of BRCA1 and was therefore investigated as a BC predisposing gene. In 2006, truncating mutations were identified in BC families (8). Segregation analysis assessed an RR of BC of 2.0 (95% CI 1.2�C3.2), although there are reports of higher risks in some families.