An initial association analysis of 94,081 imputed rare autosomal (allele frequency ≤ 0.5%) pLOF variants identified, among other findings, several known rare variant associations with breast cancer: a frameshift variant in CHEK2 and a stop gain variant in PALB2 (see Methods and Supplementary Table 16). We also found that the burden of rare pLOF variants in BRCA2 (comprising 35 rare pLOF variants; P = 1.6 × 10−8; cumulative allele frequency in cases versus controls, 0.13% versus 0.05%) was increased among cases. The individually associated pLOF variants would not have been detected using previous reference panels (Supplementary Table 16). Other examples of rare variant association signals included associations with the burden of rare pLOF variants in USH2A and retinal dystrophies (47 rare pLOF variants; allele frequency in cases versus controls, 3% versus 0.2%), IFT140 and kidney cyst (18 rare pLOF variants; allele frequency in cases versus controls, 0.5% versus 0.1%), and MYOC and glaucoma (14 rare pLOF variants; allele frequency in cases versus controls, 0.5% versus 0.1%).
