Abstract Background: The CHEK2 (Checkpoint Kinase 2) gene plays a central role in DNA damage repair and cell cycle regulation. Germline pathogenic or likely pathogenic (P/LP) CHEK2 variants confer a moderate risk of breast cancer, especially estrogen receptor (ER)-positive subtypes, and have been associated with other malignancies, including colorectal and thyroid cancers. Despite CHEK2 being one of the most frequently mutated genes identified in hereditary cancer panels, clinical data on variant distribution, tumor characteristics, and associated malignancies remain underreported in many populations. This analysis is the largest of its kind in a Middle Eastern population. Methods: We conducted a retrospective review of breast cancer patients with germline P/LP CHEK2 mutations identified through multigene panel testing (20-gene or 84-gene panels). Testing was done at one of three accredited international reference genomic labs. Clinical variables included demographics, tumor histology and grade, hormone receptor status, treatment modalities, family history, and the presence of second primary cancers. Genetic variant analysis and co-occurrence with additional mutations were also documented. Results: Fifty-nine female CHEK2-positive breast cancer patients were identified. Median age at diagnosis was 48 years (range: 28-77), with 59.3% diagnosed at or before age 50. The majority had invasive ductal carcinoma (n=48, 81.4%) and grade 1 or grade 2 tumors (73.1%). Hormone receptor status showed that all patients were estrogen receptor (ER)-positive, while progesterone receptor (PR) positivity was observed in 86.2% of cases (n=50). HER2 overexpression was observed in 23.2% of cases. Neoadjuvant therapy was administered in 48.1% of patients, and 52.5% underwent mastectomy. Family history of cancer was reported by 33 (91.5%) patients; 81.5% had at least one relative with breast cancer. The most frequent CHEK2 variant was c.592+3AT (39.0%), followed by c.499GA (20.3%). Notably, 5 patients (8.5%) carried additional germline P/LP variants: APC I1307K (n=3), BRCA2 (n=1), and co-occurring PALB2 + RAD51D (n=1). Second primary cancers were identified in 16 (27.1%) patients and mostly were breast cancer (n=12, 20.3%) and one case each of colorectal, endometrial, pancreatic and lymphoma. Among those who underwent screening colonoscopy (n=25), 3 patients (12.0%) were diagnosed with colorectal cancer, and 3 others (12.0%) had tubular adenomas and hyperplastic polyps. Conclusions: This study provides insight into the clinical and molecular landscape of CHEK2-positive breast cancer patients in a non-Western cohort. The high prevalence of the c.592+3AT variant may suggest regional founder effects. The identification of additional actionable and the high rate of second primary cancers support the use of comprehensive multigene panels in hereditary cancer testing. These findings underscore the importance of tailored surveillance and risk-reduction strategies, including screening for second primary malignancies, in CHEK2 mutation carriers. Citation Format: H. Abdel-Razeq, H. Bani Hani, F. Tamimi, L. El Saket, S. Abdel-Razeq, B. Sharaf, H. Abu-Jaish, Y. Talab, A. Al-Atary, M. El-Atrash, T. Al-Batsh, M. Horani, L. Barakat, Y. Al-Atary, O. El Khatib. From Variant to Vigilance: Clinical Implications of CHEK2 Mutation-Associated Breast Cancer and Second Malignancies in a Non-Westrern Cohort 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 PS3-05-04.
Abdel-Razeq et al. (Tue,) studied this question.