Background Genetic testing for at-risk patients with breast cancer should be routinely offered. Knowledge generated may influence both treatment decisions and cancer prevention strategies among the patients themselves and their relatives. In this study, we report on the prevalence and patterns of germline mutations, using commercially available next-generation sequencing (NGS)-based multi-gene panels (MGP). Patients and Methods Consecutive at-risk breast cancer patients, as determined by international guidelines, were offered germline genetic testing using a 20-gene NGS-based panel at a reference lab. Samples of peripheral blood were obtained for DNA extraction and genetic variants were classified as benign/likely benign (negative), pathogenic/likely pathogenic (positive) or variants of uncertain significance (VUS). Results A total of 1310 patients, median age (range) 43 (19–82) years, were enrolled. Age ≤45 years (n = 800, 61.1%) was the most common indication for testing. Positive family history of breast, ovarian, pancreatic or prostate cancers, and triple-negative disease were among the common indications. Among the whole group, 184 (14.0%) patients had pathogenic/likely pathogenic variants; only 90 (48.9%) were in BRCA1 or BRCA2 , while 94 (51.9%) others had pathogenic variants in other genes; mostly in APC, TP53, CHEK2 and PALB2 . Mutation rates were significantly higher among patients with positive family history (p = 0.009); especially if they were 50 years or younger at the time of breast cancer diagnosis (p < 0.001). Patients with triple-negative disease had relatively higher rate (17.5%), and mostly in BRCA1/2 genes (71.4%). Variants of uncertain significance (VUS) were reported in 559 (42.7%) patients; majority (90.7%) were in genes other than BRCA1 or BRCA2 . Conclusion Pathogenic mutations in genes other than BRCA1/2 are relatively common and could have been missed if genetic testing was restricted to BRCA1/2 . The significantly high rate of VUS associated with multi-gene panel testing can be disturbing.

Background Ovarian cancer is one of the most common gynecological malignancies. Due to the absence of effective screening methods, ovarian cancer is usually diagnosed at late stages. Patients with pathogenic and likely‐pathogenic germline variants (PGVs) in BRCA1 or BRCA2 harbor elevated risk of developing both ovarian and breast cancers. Identifying PGVs may help in both cancer prevention and active disease treatment. Worldwide prevalence of PGVs varies and the matter is poorly addressed among Arab patients. Methods Patients with epithelial ovarian, fallopian tube or primary peritoneal cancers were offered the universal 20 or 84‐multi‐gene panel testing as per standard guidelines. Cascade family screening was also offered to all first and second‐degree relatives of PGV positive patients. Genetic testing was done at a referral lab using a next generation sequencing (NGS)‐based platform. Results During the study period, 152 patients, median age (range): 50 (18–79) years old, were tested. The majority ( n = 100, 65.8%) had high‐grade serous carcinoma, and 106 patients (69.7%) had metastatic disease at presentation. In total, 38 (25.0%) had PGVs, while 47 (30.9%) others had variants of uncertain significance (VUS). PGVs were mostly in BRCA1 ( n = 21, 13.8%) and in BRCA2 ( n = 12, 7.9%), while 6 (3.9%) others had PGVs in non‐ BRCA1/2 genes . PGV rates were significantly higher among 15 patients with a positive family history of ovarian cancer (60.0%, p = .022) and among 52 patients with a positive family history of breast cancer (40.4%, p = .017). Conclusions PGVs are common among Jordanian women with ovarian cancer, and mostly occur in BRCA1/2 . Given its clinical impact on disease prevention and precision therapy, universal testing should be routinely offered.

10591 Background: Germline genetic testing (GGT) has a significant impact on cancer care. While universal testing has been selectively implemented in the U.S., less is known about adoption of this approach in other ethnic groups. This study reports on GGT results among newly diagnosed cancer patients (pts) in Jordan. Methods: Jo-ECAG was a prospective study of newly diagnosed cancer pts between April 2021 and September 2022 who underwent 84 gene GGT. Patients were classified based on the 2020 National Comprehensive Cancer Network (NCCN) GGT criteria as meeting (in criteria, IC) or not meeting criteria (out of criteria, OOC). Demographics and clinical history were clinician-provided. Pts who were carriers for autosomal recessive conditions were excluded from pathogenic germline variant (PGV) count. Differences in proportions were determined using two-tailed Fisher’s exact test and the significance was set at p≤ 0.05. Results: The cohort consisted of 3,313 Arabic cancer pts, predominantly female (69.8%), with a median age of 54 at testing. Breast was the most commonly diagnosed cancer (50.4%), followed by colorectal (14.9%) and prostate (14.3%). 52% of pts tested were guidelines-based (IC). 460 PGVs were identified in 426 (12.9%) pts. PGVs were most commonly identified in APC (predominantly I1307K variant, 144 pts, 4.4%), BRCA2 (72, 2.2%), BRCA1 (36, 1.1%), CHEK2 (26, 0.8%) and ATM (25, 0.8%). While IC pts were more likely than OOC pts to have a PGV (15.7% vs 9.8%, p<0.0001), 156 (36.6%) pts with PGVs were OOC. 232 (54.5%) pts had PGVs in DNA damage response and repair/homologous recombination repair (DDR/HRR) genes, including 61 (26.3%) OOC pts. 3,602 variants of uncertain significance (VUS) were identified in 2,199 (66.4%) pts with 1,868 of these pts having only VUS results (56.4%), but the frequency in the latter group was not different between IC and OOC pts (p=0.42). Conclusions: Universal GGT of all new cancer pts was successfully implemented and led to actionable findings that would have been missed with guidelines-based testing. With the exception of an overrepresentation of APC I1307K variants, PGV rates were similar to Western ethnic groups. Over half of pts had PGVs in DDR/HRR genes that confer potential eligibility for targeted therapies and/or clinical trials. While VUS rates were high, they were similar between IC and OOC pts. Additional efforts to sequence underrepresented populations and develop variant interpretation methods agnostic to ancestry may help to mitigate these disparities.

e22535 Background: Germline genetic testing (GGT) for breast cancer (BC) has implications for surgical decision-making, treatment selection, clinical follow-up and cascade testing. As uptake of GGT increases globally, it is important to examine its impact on clinician decision-making, particularly in different ethnic groups. Methods: The Jo-ECAG Study consisted of unselected, newly diagnosed cancer patients (pts) from a single center in Jordan. Pts were classified as meeting (in criteria, IC) or not meeting (out of criteria, OOC) National Comprehensive Cancer Network (NCCN) v.1.2020 GGT criteria. Pts underwent a 84 gene test with clinician-reported outcomes collected >2 months post GGT. Analysis was limited to pts with BC. Pts with one PGV in a gene associated with autosomal recessive inheritance (“carriers”) were excluded from overall PGV count. Blank responses were considered uninformative. Descriptive statistics and Fisher’s exact test were employed. Results: 1648 (21 male) Arabic pts with BC, 36% metastatic, with a mean age at diagnosis of 50.5 were tested; 67% were IC. 212 PGVs were identified in 202 (12%) pts, with a significantly higher rate in IC vs. OOC pts (14% vs. 8%, p=0.0002). PGVs were most common in BRCA1/2 (4%), APC I1307K (4%), and other BC-associated genes such as ATM, CHEK2, PALB2 and TP53 (collectively, 3%). 2% of pts were carriers and 57% had uncertain results. Among pts with PGVs and informative responses (Table), 18% had changes to treatment (11% OOC) and 82% to surveillance/follow up (16% OOC) based on GGT results. Genetic counseling and/or GGT was recommended for relatives of >90% of PGV and carrier pts. No changes to treatment or follow-up were made for pts with negative or uncertain results. Conclusions: 1 in 8 Jordanian BC pts had a PGV identified, with a similar breakdown of PGVs observed in other ethnic cohorts, aside from a higher percentage of APC I1307K. Both treatment and surveillance/follow-up decisions were impacted by GGT results. Appropriately treatment or management was not escalated for pts with negative or uncertain results. [Table: see text]