Whole exome sequencing: the search for mutations associated with hereditary breast cancer in ethnic groups of Siberia

Hereditary breast cancer (HBC) is a heterogeneous disease caused by mutations in genes characterized by ethnic specifcity. The clinical heterogeneity of this disease signifcantly complicates its diagnosis. The use of high-throughput sequencing is one of the approaches that allow the search for genes and their variants associated with the development of HBC. The purpose of the study was to search for new genes associated with HBC in the understudied ethnic groups of Siberia by using whole exome sequencing (WES). Material and Methods. WES was performed on a cohort of 16 probands with BC (Tuvan, Yakut, Altai ethnos). The study material was genomic DNA isolated from peripheral blood leukocytes. Libraries were prepared using a BGI Optimal DNA Library Prep kit. An Agilent SureSelect Human All Exon V6 kit was used for hybridization. High-throughput sequencing was performed on a DNA nanoball sequencing platform (DNBSeq-G400). Results . In the overall group of patients with signs of HBC, pathogenic variants were detected in 12.5 % of cases (2/16). For the frst time, BRCA1 (rs80357635) pathogenic variant was identified in a young patient with metachronous BC (Yakut ethnic group). A pathogenic variant of the ATM gene (rs780619951 NM_000051:exon16:c.C2413T:p.R805X) was identified in a young patient with BC (Tuvinian ethnic group). A pathogenic variant of the TDP2 c.G4T:p.E2X, rs770844602 gene (DNA repair gene) was identified for the frst time in a Tuvan BC patient (metachronous) with a family history, but its contribution to HBC remains to be proven. The TDG gene variant (rs764159587 NM_001363612:exon7:c.536dupA:p.E179fs) found in the Tuvan ethnic group and affecting splicing (SpliceAI: 0.580) requires special attention. Conclusion . This report is the frst to describe the germinal variant in the BRCA1 (rs80357635) gene in the Yakut ethnic group. Further studies are required to confrm pathogenicity of germinal variants in non-well studied genes TDP2 , TDG in ethnic BC patients.