BACKGROUND: Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear. METHODS: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. RESULTS: The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss-of-heterozygosity of the wild-type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations. CONCLUSION: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.

BIOCEV 1st Faculty of Medicine Charles University Vestec Czech Republic

Centre for Medical Genetics and Reproductive Medicine GENNET Prague Czech Republic

Department of Biochemistry Faculty of Science Charles University Prague Czech Republic

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Genetics and Microbiology Faculty of Science Charles University Prague Prague Czech Republic

Department of Medical Genetics AGEL Laboratories AGEL Research and Training Institute Novy Jicin Czech Republic

Department of Medical Genetics Faculty of Medicine and Dentistry University Hospital Olomouc Palacky University Olomouc Czech Republic

Department of Medical Genetics GHC Genetics Prague Czech Republic

Department of Medical Genetics Pronatal Prague Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Hospital Ceske Budejovice Ceske Budejovice Czech Republic

Institute for Clinical and Experimental Medicine Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Medical Genetics University Hospital Pilsen Pilsen Czech Republic

Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Laboratory of Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

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