In a family with tumor predisposition syndrome-4 (TPDS4; 609265), originally diagnosed with Li-Fraumeni syndrome, Bell et al. (1999) identified deletion of a cytosine at nucleotide 1100 of the CHK2 gene, resulting in premature termination in the kinase domain of the CHK2 protein. This heterozygous germline mutation was present in all 3 affected family members but was absent from unaffected family members and from 100 control alleles. Affected individuals had classic Li-Fraumeni syndrome with death from breast cancer, glioma, histiocytoma, and sarcoma. Family members had wildtype p53 (191170).
Vahteristo et al. (2001) identified the 1100delC mutation in the CHK2 gene in 2 families thought to have an atypical form of Li-Fraumeni syndrome because of the lack of sarcomas and childhood cancers in affected individuals.
Meijers-Heijboer et al. (2002) found that an 1100delC variant of CHEK2, which results in truncation of the kinase activity, results in an approximately 2-fold increase of breast cancer risk in women and a 10-fold increase of risk in men.
In Finland, Vahteristo et al. (2002) found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer, as compared with the 1.4% frequency found among 1,885 population control subjects (P = 0.182). However, a 3.1% frequency was found among those 358 patients with a positive family history, giving P = 0.021 compared with population controls. Furthermore, patients with bilateral breast cancer were 6-fold more likely to be 1100delC carriers than were patients with unilateral cancer (P = 0.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 (113705) or BRCA2 (600185) mutations confirmed a significantly elevated frequency of the 1-bp deletion. Tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations showed reduced CHEK2 immunostaining. The results indicated that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer, including families with only 2 affected relatives, which are more common than families that include larger numbers of affected women.
Dong et al. (2003) found this frameshift mutation in exon 10 in 1 of 298 men with familial prostate cancer, 1 of 400 men with sporadic prostate cancer, and 4 of 178 prostate cancer tumor samples. The mutation was not found in 423 unaffected men.
Meijers-Heijboer et al. (2003) defined a subset of families with hereditary breast cancer characterized by the presence of colorectal cancer (see 114500) cases, which the authors called HBCC. The 1100delC variant was present in 18% of 55 families with HBCC, as compared with 4% of 380 families with breast cancer and without colorectal cancer. The 1100delC mutation was not, however, the major predisposing factor for the HBCC phenotype, but appeared to act in synergy with at least 1 unknown susceptibility gene.
To evaluate the breast cancer risk associated with the 1100delC variant, the CHEK2 Breast Cancer Case-Control Consortium (2004) genotyped 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in 5 countries. The 1100delC variant was found in 201 cases (1.9%) and in 64 controls (0.7%), giving an estimated odds ratio of 2.34. There was some evidence of a higher prevalence of the 1100delC variant among cases with a first-degree relative affected with breast cancer (odds ratio 1.44) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis. These results confirmed that the 1100delC variant confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results were consistent with the hypothesis that the 1100delC variant multiples the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer.
Comparing data for 34 breast cancer patients with a germline 1100delC mutation with those for 102 breast cancer patients without this mutation, de Bock et al. (2004) concluded that carrying the 1100delC mutation is an adverse prognostic indicator. Mutation carriers more frequently had a female first- or second-degree relative with breast cancer and had a more unfavorable prognosis regarding the occurrence of contralateral breast cancer and distant metastasis-free survival.
Johnson et al. (2005) found that relatives of bilateral breast cancer cases who were wildtype for CHEK2 had 3 times the population risk of female breast cancer, twice the risk of prostate cancer, and a large excess of male breast cancer. Relatives of those who were carriers of CHEK2*1100delC had an even higher risk of breast cancer and prostate cancer. The results were interpreted as indicating a multiplicative interaction between CHEK2*1100delC and other unknown susceptibility genes. They suggested that bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast cancer genes.
Cybulski et al. (2006) identified the 1100delC mutation in 14 (0.8%) of 1,864 Polish men with prostate cancer, in 3 (1.2%) of 249 Polish men with familial prostate cancer, and in 12 (0.2%) of 5,496 healthy controls. Data analysis yielded an odds ratio of 5.6 for familial prostate cancer in carriers of the 1-bp deletion. The authors determined that it is a founder mutation.
Muranen et al. (2017) genotyped 39,139 breast cancer patients (of whom 624 were 1100delC carriers) and 40,063 healthy controls (of whom 224 were 1100delC carriers) from 32 Breast Cancer Association Consortium studies and analyzed the combined risk effects of CHEK2-1100delC and 77 common variants as a polygenic risk score (PRS) and pairwise interactions. The PRS conferred odds ratios of 1.59 (95% CI, 1.21-2.09) per standard deviation for breast cancer for CHEK2-1100delC carriers and 1.58 (1.55-1.62) for noncarriers. There was no evidence of deviation for the multiplicative model. The OR for the highest quintile was 2.03 (0.86-4.78), placing them in the high-risk category, and the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk at the population average.
Breen et al. (2022) found that heterozygotes for the c.1100delC variant had an individual risk of colorectal cancer of 0.39% by age 40 to 45 years and thus recommended decreasing their age to initiate routine colonoscopy to age 40.
