BACKGROUND The rarity of mutations in PALB2, CHEK2 and ATM
make it difficult to estimate precisely associated cancer risks.
Population-based family studies have provided evidence that at least
some of these mutations are associated with breast cancer risk as high
as those associated with rare BRCA2 mutations. We aimed to estimate
the relative risks associated with specific rare variants in PALB2,
CHEK2 and ATM via a multicentre case-control study.
METHODS We genotyped 10 rare mutations using the custom iCOGS
array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2
c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and
c.1343T>G and ATM c.7271T>G. We assessed associations with
breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542
cases and 23 491 controls) cancer risk, for each variant.
RESULTS For European women, strong evidence of association with
breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95%
CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI
1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI
1.42 to 85.7, p=0.0012). We also found evidence of association with
breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26
(95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5)
and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence
for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03
(95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2
c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for
any of these variants.
CONCLUSIONS This report adds to accumulating evidence that at least
some variants in these genes are associated with an increased risk of
breast cancer that is clinically important.