title: 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.
authors.affiliation: Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Schutte
authors.forename: Sheila
authors.initials: S
authors.lastname: Seal
authors.forename: Rita
authors.initials: R
authors.lastname: Barfoot
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.forename: Marijke
authors.initials: M
authors.lastname: Wasielewski
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.forename: Carel
authors.initials: C
authors.lastname: Meijers
authors.forename: Frans
authors.initials: F
authors.lastname: Lohman
authors.forename: Jan
authors.initials: J
authors.lastname: Klijn
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D064447:Checkpoint Kinase 2; D005060:Europe; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009656:North America; D015345:Oligonucleotide Probes; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D017384:Sequence Deletion
chemical_list: D015345:Oligonucleotide Probes; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases