Abstract PS3-02-07: Co-occurring pathogenic variants in patients with breast cancer

Abstract Background: Numerous studies have examined germline variant rates in individuals with breast cancer (BC), consistently reporting that about 5-10% carry a germline pathogenic variant (PV). Although multiple PVs in a single patient have been documented, such cases are rare and reported in small cohorts. As a result, the clinical implications of multiple PVs remain poorly understood. To address this gap we analyzed a large dataset of patients with BC who underwent germline genetic testing. Methods: The Myriad Collaborative Research Registry, containing clinical, genetic, and genomic information on over 1.2 million individuals with cancer, was queried. The registry includes data on 795,165 patients with a BC diagnosis who completed testing at a commercial laboratory between 1996 and 2025. Data was assessed using descriptive statistics to understand the prevalence and characteristics of patients with multiple PVs. Results: Of the 795,165 patients with BC, 75,491 (9.5%) patients had one PV, 1,600 (0.2%) carried two PVs, and 34 patients carried more than 2 PVs. Of the 1,600 patients with two PVs, the most common second primary diagnoses included ovarian cancer (84), colon adenomas/polyps (68), breast cancer (45), and endometrial cancer (39). In patients with two PVs, the median age at cancer diagnosis was 49 years; most patients were female (1,561) and White/Non-Hispanic (1,197). Patients with two PVs were grouped by PV risk categories in BC: high-risk, moderate-risk, and other-risk. See Table 1 for patient groupings based on risk categories. The largest subgroup (28.3%) had one high-risk and one other-risk PV. The median age at diagnosis was 48 years across most groups, increasing to 54 in the other/other-risk group. BC was the most reported family history across all groups. In groups with at least one high-risk PV, ovarian cancer was the second most reported family history. Colon cancer was the second most reported family history in all groups with at least one other-risk PV. BRCA1/BRCA2 made up 73.7% of pairings in the high/high-risk group, and ATM/CHEK2 accounted for 69.2% in the moderate/moderate-risk group. The frequency of these pairs was markedly higher than the highest frequency pairings in other groups. Notably, one-third of all patients with two PVs had a PV in MUTYH. Conclusions: Assessing patients with two germline PVs presents clinical and interpretive challenges. This study identified two PVs at a frequency of 1,600 in 795,165 (0.2%) patients with BC and highlights patterns suggesting that detailed personal and family history may aid in understanding these complex genetic profiles. Continued data collection is essential to identify subtle trends and improve risk assessment. Future research is needed on specific gene pairings to clarify phenotypic differences and refine risk stratification. The registry enabled identification of a large cohort with two PVs, laying a foundation for deeper investigation into their clinical significance. Citation Format: K. Woods, S. Cummings, F. Ademuyiwa. Co-occurring pathogenic variants in patients with breast cancer 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 PS3-02-07.