Abstract PS3-05-02: Prevalence and re-classification Variants of Uncertain Significance (VUS): experience of a breast cancer center in northeastern Mexico

Abstract Introduction: Variants of uncertain significance (VUS) are variants in the genetic code for which the impact on the protein function is unclear. VUS estimated probability in genes associated with hereditary breast and ovarian cancer (HBOC) is 23%, and the rate of reclassification varies from 19-27% depending on the population studied. It represents a challenge to medical management and surveillance decisions. Methods: From 2018 to 2024 a total of 334 VUS have been reported among 1014 breast cancer patients at the Breast Cancer Institute of Zambrano Hellion Hospital. A retrospective clinical-genomic review was conducted, including only patients with breast cancer.Data were extracted from electronic medical records, including: age at diagnosis, tumor laterality, immunohistochemical (IHC) profile, VUS-related gene(s), and family history of cancer (e.g., breast, ovarian, pancreas). For each case, we documented the gene in which the VUS was identified, whether it underwent reclassification, the final classification (pathogenic, likely pathogenic, or benign), and the time elapsed (in months) until reclassification. Results: 19 VUS were identified across multiple cancer susceptibility genes (Table 1). Of these, 9 variants were reclassified: 55% as benign and 45% as likely pathogenic. The mean time to reclassification was 26.44 ± 12.6 months (range 7-52).Table 1 summarizes the number of VUS per patient and their corresponding reclassification time. A total of 9 female breast cancer patients carriers of at least one of these VUS reclassified with or without a pathogenic variant. The average age at diagnosis was 40.3 years (SD ±5.32). All BC diagnoses were unilateral. Four patients (44%) presented with triple-negative breast cancer (TNBC) by immunohistochemistry (IHC). The most frequently involved gene was NF1, accounting for 5 variants (55%), of which 4 were reclassified as benign and 1 as likely pathogenic. BRCA2 presented 2 variants (22%), with one benign and one likely pathogenic outcome. BRCA1 and POLE each had 1 variant (11%), both of which were reclassified as likely pathogenic. Conclusions: The observed rate of reclassification may be influenced by the underrepresentation of Hispanic populations in genetic databases and limited access to genetic testing. Given the potential clinical implications of VUS in HBOC-associated genes, further investigation is essential to improve variant classification and optimize genetic counseling. These variants are increasingly reclassified through the integration of population-specific data, functional assays, co-occurrence with known pathogenic mutations, and other lines of evidence. Citation Format: M. S. Guzman-Garcia, J. E. Guzman-Garcia, V. Leitzelar-Bueso, L. F. Martinez-Caudillo, D. Aguilar-Y-Mendez, C. Villarreal-Garza. Prevalence and re-classification Variants of Uncertain Significance (VUS): experience of a breast cancer center in northeastern Mexico abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-05-02.