Variants of Uncertain Significance Add Complexity to Breast Cancer

Introduction: Breast cancer (BC) is the most common cancer in Iran. In the recent years an upward trend has been observed in the Iranian population. Early detection by molecular approaches may reduce breast cancer morbidity and mortality. Materials and methods : Peripheral blood was collected from patients who met the criteria and genomic DNA was extracted after informed consent was obtained. Identification of the genetic defect was accelerated through NGS platforms including whole exome sequencing (WES) and 21 gene panel. Putative mutations and VUS were validated by conventional Sanger sequencing and tested for co-segregation within the family. The pathogenicity of the variants was analyzed through various bioinformatics software and available databases. Results: Molecular approaches identified 45 private deleterious mutations and over 100 variants with unknown significance. All patients underwent post genetic counseling. For patients in the VUS group opting for risk-reducing surgery, genotype-phenotype correlation and segregation analysis was conducted among relatives to determine the pathogenicity of the variants.Discussion: The increasing use of multi-gene panels and advanced sequencing technologies will ascertain higher rates of VUS because more genes are being tested and most genomic loci have been far less intensively characterized. Depending on the genes tested a percentage of variants with unknown significance will be raised which means the association of the change with increased risk of breast cancer or other diseases is uncertain. Despite the dubious nature of VUS, our study concludes that VUS results should be determined in accordance with the genetic database of Iranian cohort.