In an individual with Li-Fraumeni syndrome-variant (see LFS2; 609265), Bell et al. (1999) identified a T-to-C transition at nucleotide 470 of the CHK2 gene resulting in an isoleucine-to-threonine substitution at codon 157 (I157T). This nonconservative substitution was within the forkhead homology-association domain of CHK2. The proband (who was a cigarette smoker) had developed 3 primary tumors: breast cancer, melanoma, and lung cancer.
In a study of prostate cancer (176807), Dong et al. (2003) found that the most common mutation of CHK2 was I157T, which was present in 7 of 298 men with familial prostate cancer, 6 men with sporadic prostate cancer, and 5 of 423 unaffected men. Their study indicated that this mutation is relatively common in normal healthy control individuals.
The I157T variant is present in the population of Finland at a frequency of 5.3% (Kilpivaara et al., 2004) and in the population of Poland at a frequency of 4.8% (Cybulski et al., 2004). It is present in comparable frequencies in German and Belorussian populations in which a relationship to cancer has been studied. Kilpivaara et al. (2006) screened the CHEK2 I157T variant in a population-based series of 1,042 Finnish colorectal cancer (114500) patients using restriction fragment length polymorphism. The frequency of I157T was significantly higher in CRC patients (76/972, 7.8%) than in healthy population controls (5.3%), giving an odds ratio (OR) of 1.5. The significant association of I157T with CRC was observed among patients with and without a family history of CRC. A trend toward higher variant frequency was also noted among patients with multiple primary tumors and a family history of any cancer. These observations supported a role for I157T as a susceptibility allele for multiple cancer types.
Cybulski et al. (2006) identified the I157T substitution in 142 (7.6%) of 1,864 Polish men with prostate cancer (176807), in 30 (12%) of 249 Polish men with familial prostate cancer, and in 264 (4.8%) of 5,496 healthy controls. Data analysis yielded an odds ratio of 2.7 for familial prostate cancer in carriers of the mutation. The authors determined that it is a founder mutation.
