Rare variants in XRCC2 as breast cancer susceptibility alleles.
BACKGROUND
Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation.


METHODS
The coding regions and exon-intron boundaries of XRCC2 were scanned for mutations in an international cohort of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls using various mutation scanning methods. Predictions on functional relevance of detected missense variants were obtained from three different prediction algorithms.


RESULTS
The only protein-truncating variant detected was found in a control. Rare non-protein-truncating variants were detected in 20 familial cases (0.6%) and nine healthy controls (0.6%). Although the number of variants predicted to be damaging or neutral differed between prediction algorithms, in all instances these categories were evenly represented among cases and controls.


CONCLUSIONS
Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. Variants in XRCC2 are unlikely to explain a substantial proportion of familial breast cancer.
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands. f.s.m.hilbers@lumc.nl
Florentine S
FS
Hilbers
Juul T
JT
Wijnen
Nicoline
N
Hoogerbrugge
Jan C
JC
Oosterwijk
Margriet J
MJ
Collee
Paolo
P
Peterlongo
Paolo
P
Radice
Siranoush
S
Manoukian
Irene
I
Feroce
Fabio
F
Capra
Fergus J
FJ
Couch
Xianshu
X
Wang
Lucia
L
Guidugli
Kenneth
K
Offit
Sohela
S
Shah
Ian G
IG
Campbell
Ella R
ER
Thompson
Paul A
PA
James
Alison H
AH
Trainer
Javier
J
Gracia
Javier
J
Benitez
Christi J
CJ
van Asperen
Peter
P
Devilee
D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D016366:Open Reading Frames
D004268:DNA-Binding Proteins; C113187:XRCC2 protein, human