Recently, large epidemiological and molecular studies have finally provided conclusive evidence that ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.
Mutations in BRCA1 and BRCA2 account for approximately 50% of breast cancer families with more than four affected cases, whereas exonic mutations in p53, PTEN, CHK2 and ATM may account for a very small proportion.
Breast cancer occurring in carriers of ATM variants is not associated with distinctive histopathological features and does not resemble the tumour phenotype commonly observed in BRCA1 mutation carriers.
We estimated the cumulative risk of BC in heterozygous ATM mutation carriers to be 6.02% by 50 years of age (95% credible interval: 4.58-7.42%) and 32.83% by 80 years of age (95% credible interval: 24.55-40.43%).
We have determined the spectrum and frequency of ATM missense variants in 443 breast cancer patients diagnosed before age 50, including 247 patients who subsequently developed CBC.
In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.
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).
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.
Several epidemiological studies on ataxia-telangiectasia families indicate that obligate ATM heterozygotes display an elevated risk for developing breast cancer.
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).
Eleven mutations were found in other breast cancer susceptibility genes including CHEK2 (n = 5), PALB2 (n = 2), BLM (n = 2), ATM (n = 1) and TP53 (n = 1).
Loss of heterozygosity studies suggest a causative role of the BARD1 mutation in the development of primary peritoneal cancer, but fail to confirm an association between germline ATM mutations and breast cancer development in this family.