an investigation of the association of genetic susceptibility risk with somatic mutation burden in breast cancer background genomewide association studies have reported nearly 100 common germline susceptibility loci associated with the risk for breast cancer tumour sequencing studies have characterised somatic mutation profiles in breast cancer patients the relationship between breast cancer susceptibility loci and somatic mutation patterns in breast cancer remains largely unexploredmethods we used singlenucleotide polymorphism snp genotyping array data and tumour exome sequencing data available from 638 breast cancer patients of european ancestry from the cancer genome atlas tcga project we analysed both genotype data and when necessary imputed genotypes for 90 known breast cancer susceptibility loci we performed linear regression models to investigate possible associations between germline risk variants with total somatic mutation count tsmc as well as specific mutation types we examined individual snp genotypes as well as a multisnp polygenic risk score prs models were statistically adjusted for age at diagnosis stage oestrogenreceptor er and progesteronereceptor pr status of breast cancer we also performed stratified analyses by er and pr statusresults we observed a significant inverse association p875 106 fdr0001 between the risk allele in rs2588809 of the gene rad51b and tsmc across all breast cancer patients for both er and er tumours this association was also evident for different types of mutations the prs analysis for all patients with or without rs2588809 showed a significant inverse association p001 and 004 respectively with tsmc this inverse association was significant in er patients with the erspecific prs p002 but not among er patients for the erspecific prs p039conclusions we observed an inverse association between common germline risk variants and tsmc which if confirmed could provide new insights into how germline variation informs our understanding of somatic mutation patterns in breast cancer