Molecular Characterization of Allelic Expression of the BRCA1 2 Founder del9-12 Pathogenic Variant and Its Potential Clinical 3 Relevance in Hereditary Cancer

The hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition thatincreases the risk of breast cancer by 80% and ovarian cancer by 40%. The most common pathogenicvariants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutationsalong the gene sequence. The prevalence of specific PVs in BRCA1 is increased across populationsdue to the effect of founder mutation. Therefore, when a founder mutation is identified, it becomeskey to be studied to improve cancer risk characterization and effective screening protocols. The onlyfunder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1(BRCA1del9-12), and its description focuses on the gene sequence, but no transcription profiles havebeen performed in individuals who carry it. In this study, we described the transcription profile in cancer patients and healthy individuals heterozygous for PV BRCA1del9-12 by analyzing the differ-ential expression of both alleles when compared with the homozygous BRCA1 control group usingRT-qPCR, and described the isoforms produced by the BRCA1 wild-type and BRCA1del9-12 allelesusing nanopore long-sequencing. Using the Kruskal-Wallis test, our results evidenced similar tran-script expression in the wild-type allele between the healthy heterozygous and the homozygousBRCA1 control group. An association between recurrence and an increased expression in both al-leles in HBOC patients was also observed. Analysis of the sequences showed four wild-typeisoforms with diagnostic potential for discerning individuals who carried the PV BRCA1del9-12 andidentified which of them had developed cancer.