P527: Concordance analysis of monozygotic twin gestations with SNP technology identifies discrepant chromosome findings

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Methods: We performed a retrospective analysis on de-identified data from individuals who received a hereditary cancer test between October 2021 to October 2022 in a commercial lab.Variants that were predicted to impact splicing were further subjected to RNA-sequencing and data analysis.Intronic, missense, and synonymous variants were analyzed to assess whether RNA-sequencing data impacted variant classification.Results: A total of 236 variants, in 41 genes, that were initially classified as a VUS and were predicted to impact splicing were subjected to RNA sequencing.RNA sequencing results resolved 22.0% (52/236) of the VUSs analyzed, with 7.2% (17/236) of the VUSs updated to likely pathogenic and 14.8% (35/236) VUSs downgraded into not reportable.The remaining 184 VUSs (78.0%, 184/236) were unchanged.Among the variants that were upgraded from VUS to Likely pathogenic, 70.6% (12/17) were identified as clinically actionable genes and included ATM, AXIN2, BRCA1, BRCA2, BRIP1, PALB2, and RAD51C.The variant types in the study included intronic variant, missense variant, and synonymous variant.Interestingly, missense variants were the most frequently upgraded variants, with 8.2% (6/73) upgraded from VUS to likely pathogenic, followed by intronic variants and synonymous variants with 7.2% (10/139) and 4.2% (1/24) upgraded to likely pathogenic, respectively.Additionally, 50.0%(12/24) of synonymous variants and 16.5% (23/139) of intronic variants were downgraded from VUS into not reportable, whereas no missense variants were downgraded from VUS to likely benign or benign.Conclusion: The identification of VUSs associated with NGS-based DNA testing poses a great challenge to the hereditary cancer genetic testing field.RNA sequencing has become a robust assay that couples the power of DNA sequencing with gene expression analysis to facilitate the interpretation of variants that play a regulatory role in RNA splicing.Here we show that 22% of VUSs that were predicted to impact splicing were updated and solved by RNA sequencing.Additionally, our data show that missense variants were most frequently updated and synonymous variants were most frequently downgraded.These VUSs were either upgraded to likely pathogenic due to the potentially significant impact on RNA splicing that could result in deleterious effect on the gene products, or downgraded to not reportable as the RNA data revealed the variant to have no impact on RNA splicing.This study underscores the utility of RNA sequencing to detect both intronic variants and coding variants that affect RNA splicing, and could have an impact on cancer risk assessment management and treatment.

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