16. Ulusal Tıbbi Genetik Kongresi, Antalya, Turkey, 4 - 08 December 2024, pp.253
Background: Variants of uncertain significance (VUS) complicate genetic testing by limiting the clinical decision-making process. Providing clear counseling about the uncertainty and implications of VUS is important to reduce patient anxiety and ensure appropriate management, particularly in cases of suspected hereditary cancer. This study aimed to reanalyze VUS detected in familial cancer NGS panels conducted between 2020-2022, in order to evaluate classification changes. Methods and Results: A total of 147 patients with VUS mutations were identified. After excluding patients with multiple VUS or additional pathogenic variants and combining identical variants, 62 unique VUS were reanalyzed. Reanalysis was performed using QCI (QIAGEN Clinical Insight Interpret 9.3.2.20240813), Franklin ACMG classification, and ClinVar to compare with the initial variant reports. Four variants were reclassified from VUS to likely pathogenic, and six variants were reclassified as likely benign. QCI reclassified 13 variants, Franklin reclassified 9 variants, while ClinVar did not reclassify any VUS. However, ClinVar recorded 10 previously unreported variants as new VUS. Discussion: While QCI and Franklin took a more flexible approach in the reanalysis, ClinVar appeared to adopt a more conservative stance. This difference highlights the importance of using multiple databases in variant interpretation. It is generally recommended that patients with VUS mutations be followed up every 1 to 2 years. Despite the fact that more than two years had passed since the reporting of most variants in our study, no classification changes were observed. As data sets grow with new studies, we hope that variant reclassification will become more fast and effective. This study emphasizes the need for long-term follow-up of VUS and the importance of extensive, continuously updated data pools for more reliable reassessment of VUS. Keywords: bioinformatic, familial cancer, VUS