Rare, protein-truncating variants in <i>ATM</i>, <i>CHEK2</i> and <i>PALB2</i>, but not <i>XRCC2</i>, are associated with increased breast cancer risks.

Abstract

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 <i>ATM</i>, <i>CHEK2</i>, <i>PALB2</i> and <i>XRCC2</i>, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. 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 <i>in silico</i> algorithms. Truncating variants in <i>PALB2</i> (OR=4.69, 95% CI 2.27 to 9.68), <i>ATM</i> (OR=3.26; 95% CI 1.82 to 6.46) and <i>CHEK2</i> (OR=3.11; 95% CI 2.15 to 4.69), but not <i>XRCC2</i> (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in <i>ATM</i> and <i>CHEK2</i> were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in <i>PALB2</i> were associated with similar risks for both subtypes. There was also some evidence that missense variants in <i>ATM</i>, <i>CHEK2</i> and <i>PALB2</i> may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect. Truncating variants in <i>PALB2</i> are associated with a higher risk of BC than those in <i>ATM</i> or <i>CHEK2</i>. A substantial risk of BC due to truncating <i>XRCC2</i> variants can be excluded.