Women harboring pathogenic variant (PV) in the BRCA1 or BRCA2 genes (= BRCA) have an elevated lifetime risk for breast cancer (BC). One of the main options for active BC risk reduction is bilateral risk-reducing mastectomy (RRM). Understanding the factors influencing that decision is important for genetic-counselling and risk mitigation strategy planning. A structured questionnaire was circulated to BRCA carriers, members of the Good Genes NGO in Israel. Data on RRM uptake and timing, factors previously reported to be associated with decision to undergo RRM (e.g., psychosocial, family history, counselling/health-system factors) were obtained. Comparison between carriers who elected to undergo RRM with those who opted for early detection schemes were performed using logistic regression and chi square statistical analyses. Of cancer free women (n = 391), 272 (69.6

BACKGROUND AND OBJECTIVE:BRCA1 and BRCA2 pathogenic germline variants (PGVs) are associated with higher risk of prostate cancer (PC). The IMPACT study evaluated the utility of targeted prostate-specific antigen (PSA) screening in BRCA1/BRCA2 PGV carriers. Here we report outcomes after five rounds of PSA screening in IMPACT. METHODS:Between 2005 and 2015, 3063 participants aged 40-69 yr (median 54 yr) were recruited from 65 centres in 20 countries in two cohorts: (1) BRCA1/BRCA2 PGV carriers (915 BRCA1, 901 BRCA2); and (2) age-matched noncarriers for a familial PGV (727 BRCA1 and 520 BRCA2 noncarriers). Annual PSA screening was performed, with PSA >3.0 ng/ml used as the indication for prostate biopsy. Our aim was to identify differences by PGV status in (1) the incidence of PC and of clinically significant PC (csPC; grade group ≥2) and (2) tumour stage and characteristics after five screening rounds. KEY FINDINGS AND LIMITATIONS:There was no statistically significant difference in PC incidence between BRCA1/BRCA2 PGV carriers and noncarriers. csPC incidence was significantly higher for BRCA2 PGV carriers than for noncarriers (3.1% vs 1.3%; p = 0.04). Among men with PC, the proportion of tumours with National Comprehensive Cancer Network intermediate unfavourable/high risk was higher in the BRCA1/BRCA2 PGV groups versus the corresponding group without PGVs (BRCA2: 65% vs 32%, p = 0.029; BRCA1: 56% vs 18%, p = 0.0017). There were no T4 or metastatic PC cases. Pathology after radical prostatectomy revealed tumour upgrading for 7/23 (26%) BRCA1 PGV carriers and 10/34 (26%) BRCA2 PGV carriers, with no tumour upgrading for men without PGVs. Study limitations include the biopsy compliance rate and changes in PC diagnostic pathways since 2005. CONCLUSIONS AND CLINICAL IMPLICATIONS:Annual PSA screening in BRCA2 PGV carriers confirmed a higher incidence of csPC and detection of clinically relevant tumours in comparison to noncarriers. For the first time, we confirm that PSA screening in BRCA1 PGV carriers results in early detection of NCCN IR-U/HR PC. Systematic PSA screening is recommended for BRCA2 PGV carriers and should be considered for BRCA1 PGV carriers.

BACKGROUND:Penetrance of breast cancer (BC) among women who carry pathogenic variants (PVs) in BRCA1 is incomplete, and the age at BC diagnosis varies considerably, even among carriers of the same PV, suggesting the involvement of genetic and non-genetic risk modifying factors. Polygenic Risk Score (PRS) models based on common sequence variants account for less than 10% of the total risk variability among BRCA1 PV carriers, indicating that further genetic modifiers remain to be identified. METHODS:Here, for the first time, we applied whole-exome sequencing for this challenge, investigating a cohort of 321 Israeli women carrying the BRCA1 185delAG founder PV. RESULTS:In our cohort, we found that harbouring additional putatively damaging missense variants in genes involved in innate immunity was significantly associated with earlier BC onset. The HR for carrying a missense variant in genes annotated to the top-scoring immune-related gene set NATURAL_KILLER_CELL_ACTIVATION was 3.62 (95% CI 1.96 to 6.67; p=3.8×10-5). CONCLUSION:These findings highlight a potential role for innate immune pathways as modifiers of BRCA1 penetrance and support the development of more refined, personalised risk prediction models.

Importance Risk-reducing bilateral salpingo-oophorectomy is recommended to substantially lower ovarian cancer risk in women carrying BRCA1 or BRCA2 pathogenic variant (PV). The use of hormone replacement therapy (HRT) after risk-reducing bilateral oophorectomy (RRBO), although generally recommended, remains debated due to concerns about its possible role in breast cancer (BC) risk. Objective To assess the possible association between HRT use and BC incidence after RRBO in women harboring a limited range of germline BRCA PVs. Design, Setting, and Participants This retrospective multicenter cohort study was conducted at 3 medical centers, including both referral and primary care facilities, in Israel. Cancer-free women (aged ≥18 years) with BRCA1 PV or BRCA2 PV, with no prior mastectomy, who underwent RRBO between January 1, 2000, and December 31, 2024, and who had at least 1 year of follow-up after RRBO were included. Exposures HRT use after RRBO. Main Outcomes and Measures First diagnosis or incidence of invasive BC. BC diagnoses were ascertained through pathology reports and diagnostic codes used in the electronic health records; some were confirmed via participant interviews. HRT use was assessed through medical records, pharmacy dispensing data, clinic visits, and telephone interviews. Cox proportional hazards regression models, with HRT modeled as a time-varying covariate, evaluated the associations with BC risk while adjusting for potential confounders. Results A total of 919 women (mean [SD] age at RRBO, 47.6 [8.9] years) were included, of whom 496 had BRCA1 PV and 423 had BRCA2 PV. During a mean (SD) follow-up of 8.8 (6.2) years, 144 women (16%) were diagnosed with invasive BC. Overall, 381 participants (42%) had ever used and 538 (58%) had never used HRT following RRBO. Ever use of HRT was not associated with increased BC risk (combined estrogen-progestin: hazard ratio [HR], 1.06 [95% CI, 0.67-1.68]; estrogen only: HR, 0.89 [95% CI, 0.48-1.63]). In duration of use analyses, each year of estrogen-only HRT was associated with a reduction in BC risk overall (HR, 0.90; 95% CI, 0.81-0.99) and a reduction among participants with BRCA1 PV (HR, 0.87; 95% CI, 0.77-0.98). Conclusions and Relevance In this cohort study of women with BRCA PV who received HRT after RRBO, estrogen-only HRT was not associated with an increased risk of BC and was associated with a lower risk of BC among women with BRCA1 PV. Combined estrogen-progestin HRT was not associated with BC risk modification.

Purpose This study aimed to expand the clinical and biological understanding of POT1 tumor predisposition syndrome and raise awareness of its broad tumor spectrum and association with ultralong telomeres. Methods We conducted a retrospective analysis of 44 individuals carrying pathogenic or likely pathogenic POT1 variants identified between 2018 and 2025. Clinical, pathologic, and demographic data were extracted from medical records. Telomere length was assessed using in-gel hybridization of telomeric restriction fragments. Results Of 44 heterozygotes, 31 had the c.233T>C; p.(Ile78Thr) variant, 8 had c.1672dup; p.(Tyr558Leufs∗6), and 5 had other frameshifting, likely loss-of-function variants. Cancer was diagnosed in 27 heterozygotes (61%), totaling 84 primary malignancies (range: 0-8 per person), with most cases (79%) occurring after the age of 50 years. Melanoma (34%) and breast cancer in females (45%) were the most common. Additional tumors included papillary thyroid carcinoma, desmoid tumors, and diverse malignant and benign neoplasms. Colonic polyps were frequent. POT1 heterozygotes with the p.(Ile78Thr) variant exhibited significantly longer telomeres than control participants, with a 62-year-old woman showing comparable or even longer telomeres than her children. Conclusion POT1 pathogenic variants confer susceptibility to a wide tumor spectrum, notably melanoma and, unexpectedly, breast cancer. At least some of these variants are linked to ultralong telomeres, consistent with findings from this study and others. These findings support incorporating POT1 into multigene panels and suggest telomere length as a potential biomarker for diagnosis.

Purpose Physical activity (PA) is associated with reduced breast cancer (BC) risk in average-risk women. Its effect on genetically predisposed high-risk women remains unclear. Methods BC cases (n = 17,409) and controls (n = 26,907) were identified from the UK Biobank with BC-related Polygenic risk score (PRS) and/or pathogenic variants (PVs) in cancer susceptibility genes (CSG), International Physical Activity Questionnaire (IPAQ) data, and/or accelerometer-measured PA. Logistic regression was used to estimate odds ratios (ORs) for developing BC. PA and PRS were stratified into tertiles (low, moderate, high), and for carriers of BRCA1/BRCA2 and other high-penetrance CSG PVs. Results PA was associated with reduced BC risk. In the full cohort, high PA conferred a 25.8%–14.8% risk reduction by accelerometer and IPAQ, respectively. BC risk-reducing effect was maximal among women with moderate PRS (46.0%–23.7% reduction by accelerometer and IPAQ, respectively). BRCA1/BRCA2 PV carriers demonstrated 50.7% risk reduction (95% CI: 6.6–73.9%). No significant effect was observed among women with low PRS or among carriers of other CSG PVs. . Conclusion Both objectively and subjectively measured PA were associated with reduced BC risk among genetically predisposed women. These findings support PA as a feasible risk-reducing strategy for high-risk women.

Retinoblastoma (RB) is typically associated with highly penetrant pathogenic sequence variants (PSVs) in the RB1 gene; however, some families exhibit low penetrance RB (LPRB). We aimed to determine the penetrance rate and identify genetic and clinical characteristics of LPRB. To that end two cohorts were analyzed: 250 genetically confirmed LPRB cases identified through systematic literature review and 78 classical germline RB (CGRB) from three international centers- Thailand, Korea, and Israel. Penetrance rate was estimated as the proportion of affected individuals among RB1 PSV carriers. Multivariate models assessed parent-of-origin effects and predictors of penetrance. PSVs were annotated with Combined Annotation Dependent Depletion (CADD) scores and mapped to pRB structural domains. LPRB penetrance ranged from 50% (125/250, non-age-adjusted, CI [43.8%-56.2%]) to 64% (125/196, age-adjusted, CI [56.8%-70.2%]). Paternal inheritance of RB1 PSV was associated with a significantly increased risk of LPRB in offspring (OR = 6.24; P < 0.0001). Clinically, LPRB were significantly more likely than CGRB to present with unilateral disease (OR = 9.3, P < 0.0001), diagnosed at an older age (13 Vs 6.5 months, P = 0.01), and affect males (OR = 2.4, P = 0.03). LPRB-associated PSVs showed lower CADD scores (OR = 1.5; P = 0.0008), indicating lower predicted pathogenicity, and were enriched in pRB's N- or C-terminal domains (OR = 3.2; P = 0.007), consistent with hypomorphic effects. In conclusion, LPRB shows a 50-64% penetrance rate, more likely to be paternally inherited, have unilateral presentation, and associated with hypomorphic RB1 PSVs in the terminal pRB regions. These findings support retitling 'low penetrance RB' to 'medium penetrance RB'.

PURPOSE:Multigene panel testing (MGPT) enables simultaneous detection of germline pathogenic/likely pathogenic variants (P/LP SV) in cancer susceptibility genes (CSG). The utility of MGPT in Israel, where most individuals eligible for oncogenetic testing undergo first-pass genotyping for predominant PSVs in the BRCA1, BRCA2, MSH2, and MSH6 genes, has not been reported. METHODS:Individuals who underwent MGPT after oncogenetic counseling between October 2013 and December 2024 were eligible for participation in this ethically approved study. NGS genotyping of 29-160 genes was performed using commercial or in-house platforms. Clinical data were obtained from records. RESULTS:Among 2990 individuals, 139 pathogenic sequence variants were detected in 39 genes in 234 individuals (7.8%). Recurring PSVs in BRCA1, BRCA2, CHEK2, ATM, MSH2, and MSH6 were noted. CHEK2 (c.592+3A>T), PMS2 (c.943C>T), and CDKN2A (c.176T>G) were identified as potentially recurring founder variants. CONCLUSIONS:The yield of MGPT in Israel, after exclusion of predominant founder PSVs, was modest. The identification of recurring PSVs warrants further investigation and potential inclusion in updated first-pass genotyping schemes.

BACKGROUND: The implementation of Israeli National screening for BRCA1/BRCA2 pathogenic variants (PVs) in 2020 has led to a significant increase in the number of unaffected female carriers who are referred to high-risk surveillance clinics (HRSCs). Lack of standardization in protocols for risk reduction and surveillance between HRSCs results in confusion and gaps in care. We aimed to identify discrepancies in existing practices and lead to policy development of a national policy for surveillance, management and risk reducing strategies in BRCA-PV carriers. METHODS: A comparative analysis of risk reduction and surveillance protocols of the nine leading HRSCs across Israel, comprising the Israeli Consortium for hereditary breast and ovarian cancer (HBOC), and multi-center meetings to develop consensus guidelines for HRSCs. RESULTS: Our analysis revealed a high level of prior consensus on critical aspects including risk-reducing mastectomy, salpingo-oophorectomy, fertility treatment, contraception, hormone replacement therapy, and general health behavior. For breast cancer (BC) imaging surveillance there was variability regarding frequency (e.g. only one HRSC offers biannual MRI for BRCA1 carriers), age limits (five centers continue in women older than 75 years), frequency during pregnancy and lactation (four HRSCs every three months and four others every six months; one does not recommend any surveillance), and surveillance post-mastectomy. For ovarian cancer (OvCa) surveillance, there was also variability: six centers recommend biannual/annual serum CA-125 level and pelvic sonography for all women, one center recommends this for all women till risk-reducing-bilateral-salpingo-oophorectomy (RRBSO), and two centers exclusively for women from age 35 till RRBSO. Surveillance recommendations for malignancies other than BC and OvCa differed greatly among centers.

Deciphering the spectrum and founder disease-causing variants (DCVs) in specific populations can shape and facilitate the diagnostic process of Lynch Syndrome (LS). The aim of this report was to comprehensively update on the genetic landscape of LS in the ethnically diverse Israeli-Jewish population. The cohort included 1080 carriers from 588 families; some from underrepresented, understudied Israeli ethnic groups recruited from 8 genetic institutes and high-risk clinics throughout the country. Variant classification was performed according to the American College of Medical Genetics criteria. A total of 157 DCVs were identified, 12 are reported here for the first time, and 9 reclassified. MSH2 DCVs were identified in 286 families (49

Introduction:The surveillance scheme for early detection of breast cancer (BC) in BRCA1/BRCA2 (=BRCA) PSV carriers in Israel includes semiannual imaging: MRI alternating with ultrasound (US) from age 25 to 29 years, with mammography (MG) replacing US from age 30 onward. The purpose of the study was to assess the added value and yield of MG/US to annual screening MRI in the surveillance scheme of young BRCA PSV carriers when BC was diagnosed ≤35 years of age. Methods:This retrospective study encompassed female BRCA PSV carriers attending the Meirav high-risk clinic at Sheba Medical Center, who were diagnosed with BC ≤35 years after joining the clinic between 2010 and 2023. Relevant clinical, radiological, pathological, genetic data, and imaging modalities used were retrieved from the computerized-archiving system, using an IRB-approved protocol. Results:Overall, 28/1,375 BRCA PSV carriers undergoing surveillance at the clinic during the study period met the inclusion criteria: 24/28 (86%) were BRCA1, and 4/28 (14%) were BRCA2 PSV carriers. In 17/28 (61%), BC was diagnosed by screening MRI and in 11/28 (39%) by MG/US (p > 0.05), of whom 7 underwent MG/US because they were either pregnant or breastfeeding. In the group diagnosed by MG/US, 5/11 had a palpable mass (interval cancers) and none in the MRI group. In 17/24 non-pregnant patients, BC was diagnosed by MRI (p = 0.03). Mean MRI-diagnosed tumor size was 12.5 ± 6.2 mm (range 5-30 mm) and 24.6 ± 13.8 mm for MG/US-based diagnosed tumors (range 6-50 mm) (p = 0.003). Conclusion:In the current study, young (≤35 years) BRCA PSV carriers diagnosed with BC were effectively diagnosed by MRI screening, and MRI-diagnosed BCs were smaller than MG/US-diagnosed BC. Thus, it seems that MRI screening is sufficient for early-stage BC detection in young, non-pregnant or breastfeeding BRCA PSV carriers with no palpable breast mass. For pregnant BRCA PSV carriers, US surveillance seems important to minimize risk for interval cancers.

Cancer cells display complex genomic aberrations that include large-scale genetic rearrangements and epigenetic modulation that are not easily captured by short-read sequencing. This study presents a novel approach for simultaneous profiling of long-range genetic and epigenetic changes in matched cancer samples, focusing on clear cell renal cell carcinoma (ccRCC). ccRCC is a common kidney cancer subtype frequently characterized by a 3p deletion and the inactivation of the von Hippel-Lindau (VHL) gene. We performed integrated genetic, cytogenetic, and epigenetic analyses on paired tumor and adjacent nontumorous tissue samples. Optical genome mapping identified genomic aberrations as structural and copy number variations, complementing exome-sequencing findings. Single-molecule methylome and hydroxymethylome mapping revealed a significant global reduction in 5hmC level in both sample pairs, and a correlation between both epigenetic signals and gene expression was observed. The single-molecule epigenetic analysis identified numerous differentially modified regions, some implicated in ccRCC pathogenesis, including the genes VHL, PRCC, and PBRM1. Notably, pathways related to metabolism and cancer development were significantly enriched among these differential regions. This study demonstrates the feasibility of integrating optical genome and epigenome mapping for comprehensive characterization of matched tumor and adjacent tissue, uncovering both established and novel somatic aberrations.

Multi-cancer predisposition gene panel testing (MCPGT) enables simultaneous deep-coverage genotyping of multiple CPGs (cancer predisposing genes) and detects germline pathogenic sequence variants (PSVs). Reported PSV carrier rates among pediatric and adolescent cancer patients range from 8 to 17.6

BACKGROUND:Li-Fraumeni syndrome (LFS) is a rare autosomal-dominant cancer-predisposition syndrome caused by germline pathogenic or likely pathogenic variants (P/LPVs) in the TP53 gene. Classical autosomal-dominant inheritance predicts a 50% transmission rate of TP53 P/LPV from each carrier parent to their offspring. However, clinical observations suggest higher-than-expected carrier proportions, indicating a potential transmission ratio distortion (TRD). The objective of this study was to investigate TRD in Israeli LFS families. METHODS:Data from families with an LFS diagnosis who were followed at Sheba Medical Center between 2015 and 2024 were reviewed. Families that had complete clinical data and offspring were included. Pedigree analyses classified carriers as confirmed, obligate, or probable. Observed carrier proportions were compared with the expected 50% rate using one-sample t-tests. RESULTS:Among 171 individuals from 20 families, 100 (58.5%) were identified as TP53 P/LPV confirmed or obligatory carriers, significantly exceeding the expected 50% inheritance rate (p = .027). A second analysis, which included 11 probable carriers, resulted in a carrier proportion of 64.9% (p < .001). TRD was observed across all phenotypic groups. No significant differences in TRD were observed by sex or variant type. CONCLUSIONS:This study revealed significant TRD in TP53 P/LPV inheritance among Israeli LFS families. A potential mechanism involves the role of TP53 in the cell cycle, in which reduced TP53 function may enhance embryonic cell proliferation, offering a survival or implantation advantage. TRD in LFS has implications for genetic counseling, reproductive decision making, and clinical management. These findings underscore the need for further research to validate TRD across diverse populations and elucidate the underlying mechanisms.

Background: BRCA1/BRCA2 female pathogenic sequence variant (PSV) carriers in Israel are offered semiannual cancer antigen 125 (CA125) serum level determination and transvaginal ultrasound until performing risk reducing salpingo-oophorectomy (RRSO), even with the lack of proven efficacy of these procedures in providing adequate early detection of ovarian cancer. Objectives: To report the results of longitudinal CA125 measurements in BRCA1/BRCA2 carriers as a tool for ovarian cancer detection in a single medical center in Israel. Methods: Asymptomatic BRCA1/BRCA2 PSV carriers attending the Meirav High Risk Clinic at Sheba Medical Center for more than 3 years were eligible. Data on specific PSV, risk reducing surgeries, and cancer diagnoses were obtained from participant records. We used chi-square and Wilcoxon-Rank tests for statistical analyses. Results: Overall, 739 (399 BRCA1, 336 BRCA2, 4 BRCA1 + BRCA2) PSV carriers were included. Mean age at the start of follow-up was 38.96 +/- 11.13 years, mean follow-up time was 7.93 +/- 2.34 years, (5860.80 women/years). Most participants (490/739 [66.3%]) had stable CA125 levels (+/- 5 U/mu l). Of participants, 61 had CA125 levels > 35 U/mu l at least twice (n=42) or at least doubling of marker levels to a minimum of 20 U/mu l (n=19), results that have led to further cancer defining investigations. Of these, 14 and 4 were diagnosed with breast and ovarian cancer, respectively. Conclusions: Longitudinally stable CA125 levels were noted in most BRCA1/BRCA2 PSV carriers and elevated levels were a poor marker for ovarian cancer development. IMAJ 2025; 27: 297-300

Benign breast disease (BBD), particularly with proliferative changes, is a risk factor for breast cancer (BC) development in average risk women. There is a paucity of data on high-risk, BRCA1 and BRCA2 pathogenic variants (PVs) carriers. Female BRCA1 and BRCA2 PV carriers treated at the Meirav Clinic, Sheba Medical Center between May 2011 and December 2024 were eligible. Data on in-hospital breast biopsies were retrieved following an ethically approved protocol. Statistical analyses included χ2 test (categorical variables) Mann–Whitney U test (continuous variables) and logistic regression for multivariate analysis. Overall, 1466 women (849 BRCA1 PV carriers) were monitored over 10,113 women/years. A total of 1453 biopsies were carried out in 454 participants (range 1–8 biopsies), with the majority (76.3

10604 Background: Li-Fraumeni Syndrome (LFS) [OMIM #151623] is an autosomal dominant cancer predisposition syndrome caused primarily by germline pathogenic (PV) or likely pathogenic variants (LPV) in the TP53 gene. Classical autosomal dominant (AD) inheritance predicts a 50% risk of inheritance for offspring of TP53 PV/LPV carriers. However, clinical observations in Israeli LFS families suggest a higher-than-expected prevalence of TP53 PV/LPV carriers among offspring. This study aims to further investigate this phenomenon. Methods: Relevant clinical data from 36 LFS families followed at Sheba Medical Center's high-risk clinic (2015–2024) were reviewed under an IRB-approved protocol. Twenty families met inclusion criteria after excluding those with incomplete clinical data or carriers without offspring. Detailed pedigree analyses were conducted to determine the carrier status of all offspring of confirmed and obligate TP53 mutation carriers. Probable carriers were defined as individuals who fulfilled two criteria: (1) a diagnosis of an LFS-associated malignancy, and (2) being a first-degree relative of a confirmed carrier. Deceased parents with LFS-associated malignancies, whose partners had normal TP53 sequencing and whose offspring tested positive for TP53 PV/LPV, were also considered obligate carriers. A t-test was used to compare the observed proportion of TP53 PV/LPV carriers among offspring with the expected 50% inheritance rate for AD conditions. Results: A total of 174 individuals met the study criteria and were either genotyped for the family-specific TP53 PV/LPV or assigned obligatory or probable carrier status. Of these, 115 (66.1%) were identified as TP53 PV/LPV carriers, either through genotyping (n= 87), obligatory (n= 13) or probable carrier designation (n= 15). This observed proportion was significantly higher than the expected 50% based on AD inheritance (p<0.0001). Out of the TP53 PV/LPV carriers, 67 (58.3%) individuals were healthy at the time of genotyping, and 62 (53.9%) were male. Conclusions: Our findings reveal a significant skewing of TP53 variant inheritance in Israeli LFS families, with a higher-than-expected prevalence of carriers among offspring. To our knowledge, this phenomenon has not been previously reported in LFS. A potential mechanism for this skewing may involve TP53's role in cell cycle regulation and apoptosis. Reduced TP53 protein levels could confer a selective advantage during early embryonic development by enhancing cell proliferation, potentially improving embryonic survival and implantation success. If corroborated in larger and ethnically diverse LFS cohorts, this finding could have implications for genetic counseling, particularly in reproductive decision-making for LFS families. Further research is needed to validate these findings and explore the underlying biological mechanisms driving this skewing.

To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with 50

Abstract In Ashkenazi Jews (AJ) three recurring pathogenic sequence variants (PSVs) are detected in ~2.5% of the general population in the BRCA1 (c.68_69del = 185delAG, c.5266dup = 5382insC), and BRCA2 (c.5946del = 6174delT). Population-based screening for these PSVs in AJ women is part of the health basket in Israel. To assess the feasibility and outcome of BRCA genotyping in the Jewish population of Uruguay, AJ in the greater Montevideo area were recruited using ethically approved protocol and without pretest counseling were genotyped for the three predominant AJ PSVs in the BRCA genes. Independently confirmed PSV carriers were counseled, and genetic testing was offered to additional family members. Overall, 327 participants were enrolled: 312 (95%) female, 261 (80%) had all four grandparents AJ, and 14 (4%) women were breast cancer survivors with a mean age ± standard deviation (SD) 50 ± 11.5 years. The BRCA1 c.68_69del PSV was detected in three cancer free participants (0.92%, CI 95% 0.31-2.6), all with a suggestive family history. No carriers of the other two recurrent PSVs were detected. Online oncogenetic counseling was provided for all carriers. In conclusion, the rate of the BRCA1 c.68_69del PSV was similar with the rate in other AJ communities. AJ population BRCA genotyping screens in Uruguay seem feasible and should be promoted. Pedigrees of the carrier cases (a-c) Citation Format: Cecilia Castillo, Natalia Camejo, Nora Artagaveytia, Lucia Brignoni, Yael Laitman, Alfonso Cayota, Gabriel Krygier, Lucia Delgado, Eitan Friedman. Population-based screening of Uruguayan Ashkenazi Jews for recurrent BRCA1 and BRCA2 pathogenic sequence variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-02.