MO2-11-3BRCA variant classification is improved by Japanese SNP data and correlate with response to PARP inhibition in MH GUIDE

Abstract Background The BRCA1/2 genes have emerged as critical biomarkers, particularly for patients with hereditary breast and ovarian cancer (HBOC). MH BRCA classifies variants based on ACMG guidelines. Clinical interpretation of NGS results by MH GUIDE provides clinicians with treatment recommendations to cancer based on expert curated biomarker knowledge. Methods MH BRCA was compared to the clinical interpretation of three Japanese HBOC studies. Population-frequency (PF) data from the 1000 Genomes Project (1000G) and the Japanese genome cohort of Tohoku Medical Megabank Organization (ToMMo) were analyzed. Based on functional evidence for DNA damage response, we correlated the ACMG index with the predicted response to PARP inhibition by MH GUIDE. Finally, BRCA classifications of 350 patients with breast and/or ovarian cancer sequenced at the Yamanashi Central Hospital (YPCH) were compared to MH BRCA. Results MH BRCA using the integrated ToMMo data revealed 40% increased accuracy in benign classification. The Japanese-cohort in 1000G represents Conclusion We enhanced the performance of MH BRCA for Japanese HBOC patients by integrating data from the ToMMo database. Our collaboration with YPCH revealed that MH BRCA supports a standardized process for assessment of pathogenicity. Contextualizing of MH BRCA classifications with MH GUIDE supports the treatment strategy of PARP inhibition with the benefit on fine-resolution of hypermorphic and hypomorphic BRCA mutations.