Some specific missense and protein truncating variants of ATM have been reported to confer increased breast cancer risk, but the magnitude of this risk remains uncertain.
Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.
For the ATM IVS1+19A>T polymorphism, a significant association with breast cancer risk was found in the allele contrast model (C vs. T: OR = 1.60; 95% CI 1.02-2.52).
Mutations in genes such as TP53 and PTEN have also been linked with high risk for breast cancer within specific cancer syndromes and rare germline variants in genes such as CHEK2 and ATM have been found to confer modest risk to breast cancer.
These include linkage analysis for mapping out BRCA1 and BRCA2, mutational screening of candidate risk genes like CHEK2, ATM, BRIP1 and PALB2, which are associated with an intermediate level of breast cancer risk.
This possible excess risk of breast cancer associated with ATM heterozygosity constitutes the basis for several genetic epidemiological studies designed to clarify the role that the ATM gene plays in the etiology of breast and other cancers.
These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC.
Our study reveals no apparent association of common ATM variants with breast cancer risk and underscores the importance of replication using independent samples to reduce type I errors in association studies of low-penetrance genetic factors.
Allelic heterogeneity has made it difficult to confirm the role of ATM, the gene mutated in A-T, for breast cancer susceptibility in the general population.
Thus, our procedure identified at least one allelic variant of ATM associated with breast cancer, and indicated that the ATM locus may interact with HRAS1.
For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10<sup>-5</sup>), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10<sup>-8</sup>) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012).
The frequencies of genotypes for ACE were: DD, ID and II (in %: cases: 60; 20; 20; controls: 46; 37; 17; p=0.019, chi(2)); and for AT(1)receptor were:AA,AC and CC (in %: cases: 65; 30; 5; controls: 51; 44; 5; p=0.114, chi( 2)).The results suggested that the A1166C polymorphism was not associated with breast cancer risk.
These data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers.