Functional analysis of a splicing variant of the DOCK8 gene in a patient with breast cancer (Buryat ethnicity).

BRCA1/2 founder mutation have been detected in various populations and ethnicities. Molecular diagnosis of HBOC remains challenging for populations where founder mutations have not yet been identified. There are limited data on hereditary BC mutations in ethnic groups of Siberia. The purpose of this study was to find new hereditary breast cancer (BC) variants in the understudied Buryat ethnic group by using WES data and DNA construct for their subsequent validation.<br /><br />Methods: Our study included a 52-year-old Buryat BC patient with a family history of BC (sister with BC). To identify novel as well as previously described variants, obtained by WES, we used the OpenCRAVAT mutation impact scoring algorithm (comprehensive knowledge base). For variants requiring further study, the DNA construct method was used. <br /><br />Result: According to WES data, no pathogenic variants were found in a 52-year-old Buryat BC patient with a family history of BC. The patient was found to have rare variants of unknown significance (MLH1 c.C550T:p.R184C and FANCI c.A1111G:p.S371G) and c.986C>T DOCK8 gene variant (as secondary findings). In silico analysis indicated that only c.986C>T variant of DOCK8 gene may affect splicing (a key immunity gene could act as a tumor suppressor). Electrophoresis of PCR fragments obtained using cDNA as a template showed that in the presence of the c.986C>T variant, the length of the PCR product was 60 bp less than in the case of the reference sequence of this region. <br /><br />Conclusion: We suggest that the combined carriage of the c.A1111G mutation of the FANCI gene and c.986C>T DOCK8 gene identified in this patient may likely increase the risk of developing BC. Our functional data indicate a potential impact c.986C>T variant of the DOCK8 gene on splicing. The role of the c.986C>T variant in BC pathogenesis and its prevalence in Buryats ethnic group remain to be elucidated.