Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls.
BACKGROUND
Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.


METHODS
We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium.


RESULTS
Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P(trend) = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P(trend) = 0.02).


CONCLUSIONS
In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.


CONCLUSIONS
Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
Fletcher
Olivia
O
British Breast Cancer Study, The Breakthrough Breast Cancer Research Centre, London, United Kingdom. olivia.fletcher@icr.ac.uk
Johnson
Nichola
N
dos Santos Silva
Isabel
I
Orr
Nick
N
Ashworth
Alan
A
Nevanlinna
Heli
H
Heikkinen
Tuomas
T
Aittomäki
Kristiina
K
Blomqvist
Carl
C
Burwinkel
Barbara
B
Bartram
Claus R
CR
Meindl
Alfons
A
Schmutzler
Rita K
RK
Cox
Angela
A
Brock
Ian
I
Elliott
Graeme
G
Reed
Malcolm W R
MW
Southey
Melissa C
MC
Smith
Letitia
L
Spurdle
Amanda B
AB
Hopper
John L
JL
Couch
Fergus J
FJ
Olson
Janet E
JE
Wang
Xianshu
X
Fredericksen
Zachary
Z
Schürmann
Peter
P
Waltes
Regina
R
Bremer
Michael
M
Dörk
Thilo
T
Devilee
Peter
P
van Asperen
Christie J
CJ
Tollenaar
Rob A E M
RA
Seynaeve
Caroline
C
Hall
Per
P
Czene
Kamila
K
Humphreys
Keith
K
Liu
Jianjun
J
Ahmed
Shahana
S
Dunning
Alison M
AM
Maranian
Melanie
M
Pharoah
Paul D P
PD
Chenevix-Trench
Georgia
G
Beesley
Jonathan
J
Bogdanova
Natalia V
NV
Antonenkova
Natalia N
NN
Zalutsky
Iosif V
IV
Anton-Culver
Hoda
H
Ziogas
Argyrios
A
Brauch
Hiltrud
H
Ko
Yon-Dschun
YD
Hamann
Ute
U
Fasching
Peter A
PA
Strick
Reiner
R
Ekici
Arif B
AB
Beckmann
Matthias W
MW
Giles
Graham G
GG
Severi
Gianluca
G
Baglietto
Laura
L
English
Dallas R
DR
Milne
Roger L
RL
Benítez
Javier
J
Arias
José Ignacio
JI
Pita
Guillermo
G
Nordestgaard
Børge G
BG
Bojesen
Stig E
SE
Flyger
Henrik
H
Kang
Daehee
D
Yoo
Keun-Young
KY
Noh
Dong Young
DY
Mannermaa
Arto
A
Kataja
Vesa
V
Kosma
Veli-Matti
VM
García-Closas
Montserrat
M
Chanock
Stephen
S
Lissowska
Jolanta
J
Brinton
Louise A
LA
Chang-Claude
Jenny
J
Wang-Gohrke
Shan
S
Broeks
Annegien
A
Schmidt
Marjanka K
MK
van Leeuwen
Flora E
FE
Van't Veer
Laura J
LJ
Margolin
Sara
S
Lindblom
Annika
A
Humphreys
Manjeet K
MK
Morrison
Jonathan
J
Platte
Radka
R
Easton
Douglas F
DF
Peto
Julian
J
D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases
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