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F-box proteins participate in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins, such as cyclin D1 as target of FBXW8. To investigate the spectrum of FBXW8 germ-line mutations in patients with breast cancer and healthy controls, we analyzed the whole FBXW8 coding region and flanking untranslated portions in germ-line DNA samples of 91 breast cancer patients and 277 healthy controls using next-generation amplicon sequencing. Five missense variants, one splice site variant, one frameshift variant, one synonymous variant, and one variant in the 3'-UTR were identified. Frameshift mutation FBXW8 c.1312_1313delGT was considered functionally relevant and was investigated for its potential association with breast cancer risk through subsequent genotyping in two hospital-based breast cancer case-control series from Belarus and Germany, respectively, comprising a total of 2740 breast cancer cases and 2174 controls. The mutation was found in 30 cases and 23 controls with an adjusted Odds Ratio 1.02 (95% CI 0.59-1.77; p = 0.94) in the combined analysis. There was no statistically significant difference when patients were stratified by ER status, PR status, age at diagnosis, ductal histology, contralateral status, family history or tumor grade. Altogether, our data exclude clinically actionable breast cancer risks above two-fold for the FBXW8 c.1312_1313delGT mutation, although larger studies would be needed to exclude low-penetrance associations., (Copyright © 2017. Published by Elsevier Inc.)