Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility

Abstract

We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with three or more cases of breast cancer. We identified one novel germline variant, R117G, in two separate families. To evaluate the possible association of R117G and two germline variants reported elsewhere, R145W and I157T with breast cancer, we screened 737 BRCA1/2-negative familial breast cancer cases from 605 families, 459 BRCA1/2-positive cases from 335 families, and 723 controls from the United Kingdom, the Netherlands, and North America. All three variants were rare in all groups, and none occurred at significantly elevated frequency in familial breast cancer cases compared with controls. These results indicate that 1100delC may be the only CHEK2 allele that makes an appreciable contribution to breast cancer susceptibility.

Figure 1

Abridged familial pedigrees with breast cancer who were positive for CHEK2 R117G. A, Pedigrees positive for R117G, as identified in the Variant Ascertainment Set. The index individual screened is indicated with an arrow. B, Pedigrees positive for R117G, as identified in the Variant Evaluation Set; all three individuals were screened as part of the analyses. Filled symbols indicate individuals with breast cancer. Hatched symbols indicate individuals with cancers other than breast cancer. bc = breast cancer; bbc = bilateral breast cancer; crc = colorectal cancer; lu ca = lung cancer; oe ca = esophageal cancer. The age at diagnosis is indicated after the tumor type.