Analysis And Generation Database Of BRCA1/2 Variants From Chinese Population

BackgroundBreast cancer susceptibility gene(BRCA)includes BRCA1 and BRCA2.The accurate interpretation of BRCA1/2 variants becomes increasingly important in breast cancer and other related cancers including ovarian cancer,prostate cancer,pancreatic cancer and so forth.In the past decades,especially before year 2015,limitations of techniques and lack of databases and guidelines have led to possible misinterpretation of the clinical significance of sequence variants of BRCA 1/2.A published study reported reclassification of some BRCA 1/2 variants previously classified as Variants of Uncertain Significance(VUS)to likely pathogenic in breast or ovarian cancer patients from Korea.However,little is known about the situation in Chinese population.In addition,there is so far no public Chinese BRCA variation database containing the variant data derived from the Chinese population.ObjectiveThe objective of this study was to retrospective analyze BRCA 1/2 variants reported previously and generate a comprehensive BRCA variant data derived from Chinese population to make the data publicly accessible for research and clinical applications.MethodsWe retrospectively retrieved 109 publications studying about BRCA1/2 variants of Chinese population from year 1999 to year 2019(March).After excluding publications of meta-analysis and publications with missing data,72 publications were eventually retained for subsequent analysis.In total,1,351 BRCA variants(673 BRCA1 variants and 678 BRCA2 variants)derived from 42,430 Chinese cancer patients were standardized and reinterpreted using ACMG/AMP 2015 guidelines and China Expert Consensus on BRCA variant interpretation.21,100 samples were collected from 2016 to 2019.For the received samples,the Illumina platform NGS technology were used for BRCA 1/2 mutation detection.For detection of pathogenic or likely pathogenic,Sanger sequencing is used for verification.For the detected data of the three types of mutations that are pathogenic/likely pathogenic/Variants of Uncertain Significance,the corresponding content is mined according to the set database format,and developed the entire data into a MySQL database.ResultsAmong the 1,351 BRCA variants,the majority of interpretation(91.7%,1,239/1,351)remained the same as previously published.However,there were 112(8.3%,112/1,351)variants(64 BRCA1,48 BRCA2)reclassified with different categories.In addition,a total of 719 pathogenic/likely pathogenic/VUS were found in all the BRCA 1/2 mutations detected in all the samples collected clinically,of which 367 were BRCA1 mutations and 352 were BRCA2 mutations.We further developed an open access database known as easyBRCA-Chinese to host all the variants and their annotation information(http://120.77.144.1 12/EasyBRCA/#/L ogin).ConclusionsOur results demonstrated that clinical significance of not only VUS but also pathogenic/likely pathogenic variants varied from time to time in Chinese population.Of the 112 reclassifications,except the 78 variants that were reported as VUS in the original article,29 variants that were reported as conflicting or unclear classification and 5 that were reported as pathogenic/likely pathogenic were reclassified.Precise reinterpretation of BRCA1/2 variants is of crucial importance to genetic counseling or clinical decision-making for risk individuals or patients.Moreover,We have generated a BRCA database derived from Chinese population which can help us to study Chinese-specific features of BRCA variation in Chinese population.The availability of the first openaccess Chinese BRCA database provides a foundation to establish a Chinese BRCA reference database for clinical applications of prevention,surveillance,diagnosis,and treatment of BRCA-related cancer in Chinese population.