Abstract PS3-03-26: Guideline concordant surgical management of hereditary variants of uncertain significance: outcomes from a safety-net hospital

Abstract Background: Germline genetic testing is recommended for individuals with personal or family history of certain cancers, as pathogenic variants (PV) can guide cancer screening and management. Variants of uncertain significance (VUS) present clinical challenges as guidelines recommend that VUS alone should not determine cancer management or decisions about risk-reducing surgeries. VUS are disproportionately reported in non-white individuals, reflecting the historic underrepresentation in genetic reference databases. These disparities complicate genetic counseling and exacerbate inequities in cancer care. Methods: The High Risk Cancer Genetics Clinic (HRC) was established at Boston Medical Center, the region’s largest safety net hospital, to improve access to cancer screening and surveillance. We conducted a retrospective cohort study of patients with a VUS in hereditary breast and ovarian cancer (HBOC) genes and compared surgical decision-making among patients found to have VUS two years before and after HRC establishment from May 2021 to April 2025. Male patients and those with metastatic disease were excluded. Results: There were 438 patients with at least one VUS in BRCA1, BRCA2, BRIP1, TP53, PALB2, PTEN, CDH1, STK11, RAD51C, or RAD51D genes, for which PV can inform risk-reducing bilateral mastectomy (BLMa) and/or bilateral salpingo-oophorectomy (BSO). A total of 158 patients were included, and 69% had Medicaid, Medicare, or were uninsured, 78% self-identified as non-white, and 46% spoke a language other than English. After HRC, significantly more patients with HBOC VUS were referred to see genetic counselors (87% vs 96%; p=0.05) and HRC physicians (0 vs 10%, p=0.006). Before and after HRC establishment, there were no cases of BLMa among patients with a VUS who did not have breast cancer. Similarly, patients with a VUS who did not have ovarian cancer did not undergo BSO. A small proportion of breast cancer patients with a VUS had BLMa before and after HRC (5% vs 12%, p=0.64). Two patients with BRCA1 and PTEN VUS were reclassified as likely PV, and the HRC facilitated updated screening guidance that led to timely olaparib initiation and detection of localized breast cancer, respectively. Conclusion: At our safety-net hospital serving a diverse community, the management of patients with HBOC VUS has remained guideline concordant, with no risk-reducing surgeries performed solely based on a VUS result. Among breast cancer patients with an HBOC VUS who elected BLMa, all had documented counseling regarding the lack of survival benefit compared to breast conserving surgery, but chose BLMa for cosmetic or personal reasons. The integration of HRC has enabled timely re-evaluation and clinical action when a VUS is upgraded to PV. This demonstrates the value of multidisciplinary risk assessment in improving diagnostic and therapeutic outcomes for underserved populations. Citation Format: K. P. Verma, L. J. Oshry, M. Rudderman, I. Arshad, B. Moy, L. Wu. Guideline concordant surgical management of hereditary variants of uncertain significance: outcomes from a safety-net hospital [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 PS3-03-26.