TY - JOUR T1 - Rare, protein-truncating variants in <em>ATM</em>, <em>CHEK2</em> and <em>PALB2</em>, but not <em>XRCC2</em>, are associated with increased breast cancer risks JF - Journal of Medical Genetics JO - J Med Genet SP - 732 LP - 741 DO - 10.1136/jmedgenet-2017-104588 VL - 54 IS - 11 AU - Brennan Decker AU - Jamie Allen AU - Craig Luccarini AU - Karen A Pooley AU - Mitul Shah AU - Manjeet K Bolla AU - Qin Wang AU - Shahana Ahmed AU - Caroline Baynes AU - Don M Conroy AU - Judith Brown AU - Robert Luben AU - Elaine A Ostrander AU - Paul DP Pharoah AU - Alison M Dunning AU - Douglas F Easton Y1 - 2017/11/01 UR - http://jmg.bmj.com/content/54/11/732.abstract N2 - Background Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK.Methods Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms.Results Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect.Conclusions Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded. ER -