Background: Germline variants of uncertain significance (VUS) should not change surgical decision-making in breast cancer (BC) patients based on current guidelines. We sought to evaluate whether VUS may drive surgical choice in lumpectomy-eligible BC patients. Methods: A single-institution retrospective analysis included breast surgery patients (2020-2021). ‘Lumpectomy-eligible’ was defined as unilateral cT0-2 BC, excluding those with pathogenic mutations. Descriptive analyses compared those undergoing lumpectomy or bilateral mastectomy (BLMast), accounting for testing results. Multivariate analysis to predict the likelihood mastectomy receipt was limited to tested patients without pathogenic mutations using binomial logistic regression. Results: Of 741 patients, 549 (74%) were lumpectomy-eligible and 326 received genetic testing (235 negative, 91 VUS). Median age was 55.0 (26 - 84). Of those tested, 206 underwent lumpectomy, and 58 underwent BLMast. Insurance type, race, ethnicity, language, tobacco use, marital status, and axillary management did not differ between groups. Compared to lumpectomy patients, a higher proportion with a VUS (40% vs 25%, p=0.026), AJCC Stage 2 disease (41% vs 31%, p=0.023), or with ≥ 2 MRI-recommended biopsies (31.3% vs 13.8%, p=0.021) underwent BLMast. Multivariate analysis found that VUS patients were twice as likely to undergo BLMast compared to those with negative testing (OR 2.213 95% CI 1.113-4.400, p=0.023) (Table). Young patients and those with more advanced disease were also more likely to undergo BLMast. Conclusions: VUS genetic testing results may significantly influence lumpectomy-eligible patient decision-making. In an era of expanded genetic testing access, the present analysis informs the implementation of robust but accessible genetic counseling education initiatives in breast surgical oncology to decrease unnecessary mastectomies in patients with VUS.

*p-value: <0.05. 1: Ref Age ≥50. 2: Ref BMI <30. 3: Ref Tested Negative. 4: Ref DCIS. 5: Ref HBOC Criteria Not Met. Dependent Variable: Bilateral Mastectomy. Model adjusted for the following variables: BMI, Genetic Testing, Age, AJCC Stage, Diabetes, Neoadjuvant Therapy, Jewish Ancestry, Family History [meets criteria for genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome].