Abstract Background: Cancer cells frequently harbor genomic rearrangements and somatic copy number alterations that result from chromosome breaks, which vary in frequency across the genome. The distribution of breakpoint locations depends on features of the local genomic context, such as presence of certain retrotransposons. Moreover, inherited variants have been associated with specific chromosomal alterations in myeloproliferative neoplasms and in blood from cancer-free individuals. Here, we developed and applied computational methodology to broadly identify associations between inherited variants and the location of somatic breakpoints across cancers. Methods: We analyzed TCGA Affymetrix Genome-Wide Human SNP Array 6.0 data from matched tumor-normal pairs (n = 5,923 samples remaining after quality control and selecting for individuals of predominantly European ancestry). Germline genotypes were called from normal samples using Birdseed v2. Allele-specific copy number analysis using both normal and tumor samples for each individual was performed using ASCAT v2.5.1. Breakpoints were inferred as the intervals between ASCAT-called somatic chromosomal segments. We assigned individuals binary phenotypes corresponding to whether a somatic breakpoint was detected in non-overlapping 5 megabase bins of the genome. We then performed an association analysis between each phenotype and variants located on the same chromosome as the corresponding bin, adjusting for sex and ancestry via logistic regression with plink2. Analyses were performed separately for each disease type followed by a meta-analysis of association summary statistics with METAL. Results and Conclusions: We identify several candidate associations between inherited variants and the presence of somatic breakpoints in specific regions of the genome (using a p-value cutoff of 5e-8 for each phenotype). Our results suggest that heritable genetic variation may be associated with risk of development of localized chromosome breaks in somatic cells. Ongoing work is aimed at validating the putative associations (for example using data from the PanCancer Analysis of Whole Genomes study) and identifying potential mechanisms associated with putative risk alleles. Citation Format: Meng Xiao He, Sahar Shahamatdar, Amaro Taylor-Weiner, Travis Zack, Sohini Ramachandran, Eliezer Van Allen. Association of inherited variants with chromosomal breaks in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1737.