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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.

Original publication

DOI

10.1086/373965

Type

Journal article

Journal

American journal of human genetics

Publication Date

04/2003

Volume

72

Pages

1023 - 1028

Addresses

Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.

Keywords

Breast Cancer Linkage Consortium, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Protein Kinases, Oligonucleotide Probes, Pedigree, Sequence Deletion, Base Sequence, Gene Frequency, Germ-Line Mutation, North America, Europe, Female, Male, Genetic Variation, Checkpoint Kinase 2, Protein Serine-Threonine Kinases