Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility.
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.
Schutte
Mieke
M
Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
Seal
Sheila
S
Barfoot
Rita
R
Meijers-Heijboer
Hanne
H
Wasielewski
Marijke
M
Evans
D Gareth
DG
Eccles
Diana
D
Meijers
Carel
C
Lohman
Frans
F
Klijn
Jan
J
van den Ouweland
Ans
A
Futreal
P Andrew
PA
Nathanson
Katherine L
KL
Weber
Barbara L
BL
Easton
Douglas F
DF
Stratton
Michael R
MR
Rahman
Nazneen
N
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
D015345:Oligonucleotide Probes; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases