Background Approximately half of ovarian tumors have defects within the homologous recombination repair pathway. Tumors carrying pathogenic variants (PVs) in BRCA1/BRCA2 are more likely to respond to poly‐ADP ribose polymerase (PARP) inhibitor treatment. Large rearrangements (LRs) are a challenging class of variants to identify and characterize in tumor specimens and may therefore be underreported. This study describes the prevalence of pathogenic BRCA1/BRCA2 LRs in ovarian tumors and discusses the importance of their identification using a comprehensive testing strategy. Methods Sequencing and LR analyses of BRCA1/BRCA2 were conducted in 20 692 ovarian tumors received between March 18, 2016 and February 14, 2023 for MyChoice CDx testing. MyChoice CDx uses NGS dosage analysis to detect LRs in BRCA1/BRCA2 genes using dense tiling throughout the coding regions and limited flanking regions. Results Of the 2217 PVs detected, 6.3% (N = 140) were LRs. Overall, 0.67% of tumors analyzed carried a pathogenic LR. The majority of detected LRs were deletions (89.3%), followed by complex LRs (5.7%), duplications (4.3%), and retroelement insertions (0.7%). Notably, 25% of detected LRs encompassed a single or partial single exon. This study identified 84 unique LRs, 2 samples each carried 2 unique LRs in the same gene. We identified 17 LRs that occurred in multiple samples, some of which were specific to certain ancestries. Several cases presented here illustrate the intricacies involved in characterizing LRs, particularly when multiple events occur within the same gene. Conclusions Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.

e15045 Background: Molecular profiling of ovarian tumors allows for personalized disease treatment but often requires testing from multiple laboratories. This study highlights results from a molecular testing pathway that reports on germline and tumor mutations, microsatellite instability (MSI), tumor mutation burden (TMB), and homologous recombination deficiency (HRD) to guide optimal treatment selection. Methods: Samples from a consecutive prospective cohort of ovarian cancer patients were collected and tested with an HRD companion diagnostic (CDx) test (FDA-approved) that assesses genomic instability score (GIS) via a 3-biomarker signature and tumor mutation screening using a 523-gene DNA and a 55-gene RNA panel to identify clinically actionable test results using Association for Molecular Pathology (AMP) tiering. Some patients also received germline analysis via a 48-gene panel or a BRCA1/2 CDx. Clinical data (tumor stage and grade, histological subtype) were compared using logistic regression models. GIS distributions were compared using Kolmogorov-Smirnov tests. Results: To date, results from 389 eligible patients have been analyzed. Table 1 shows the primary results of molecular testing. Tumor subtype analyses revealed that high-grade serous subtype was tested most frequently (66.1%). Some less-represented subtypes (e.g., carcinoscarcoma, mucinous) appeared to have GIS distributions like high-grade serous, while others generally have low GIS. GIS distributions were significantly different in high-grade (vs moderate and vs low-grade) and stage I (vs the similar stages II-IV) tumors. Tier 1A/B mutations were observed in 16.7% of tumors; 36.9% of those were non- BRCA pathogenic variants/mutations. Distributions of histological subtype and grade were significantly different between t BRCA+ and non- BRCA samples with other Tier 1A/B mutations. Mutations were observed in 9.0% of germline tests; tumor mutation testing identified all germline variants except for a PMS2 multi-exonic deletion. Conclusions: Multi-omic testing found ~30% of ovarian cancer patients received a clinically actionable test result (HRD was the most common) and ~90% of results conferred eligibility for clinical trials. Incorporation of germline testing and RNA analysis identified unique actionable findings. A single source for comprehensive testing combined with a single integrated report facilitates rapid testing, test interpretation, and treatment choice. [Table: see text]

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e13653 Background: The HOXB13 c.251G > A (p.G84E) variant is associated with increased prostate cancer risk, possibly at younger ages. Studies on this variant have focused primarily on men, although genetic testing for hereditary cancer risk is most often performed in women. There remains a need to assess whether male and female carriers of this variant have increased risk for other cancers. Methods: We identified male and female carriers of the HOXB13 c.251G > A (p.G84E) variant among individuals referred for hereditary cancer panel genetic testing from October 2018 – December 2019. Non-carriers had no pathogenic variants in any gene or variants of uncertain significance in HOXB13. Personal and family (1st- and 2nd-degree relative) cancer histories were obtained from provider-completed test request forms. Multivariable logistic regression (MLR) models were conducted separately for males and females to estimate cancer risks for the variant as odds ratios (ORs), and 95% Wald confidence intervals (CIs) adjusted for age, ancestry and personal/family cancer history. Results: The analysis included 197,978 patients: 4.5% (8,998/197,978) male and 95.5% (188,980/197,978) female. The HOXB13 variant was present in 0.44% (40/8,998) of tested males, 45% (18/40) of whom had a diagnosis of prostate cancer. The variant was present in 0.32% (621/188,980) of tested females. Male carriers with prostate cancer were diagnosed at younger ages (median, 56; Interquartile ratio [IQR], 52, 62) than non-carriers (median, 63; IQR, 57,70), but this difference was not statistically significant. The MLR model calculated a 3.30 OR for prostate cancer in male carriers of c.251C > A ( P = 0.01; 95% CI 1.30-8.39). In an analysis combining males and females, carriers were significantly more likely to report prostate cancer in a family member than non-carriers ( P = 3.5 x 10−7; OR 1.61, 95% CI 1.34-1.93). There was no apparent association with increased risk for other cancers among carriers versus non-carriers, or among relatives of carriers compared with relatives of non-carriers. Conclusions: The HOXB13 c.251G > A (p.G84E) variant was associated with significantly increased risk of prostate cancer, confirming previously published studies. We found no evidence of association with other cancers. For unaffected male carriers, who may frequently be identified through testing of a female relative, identification of this HOXB13 variant provides an opportunity for more precise prostate cancer risk stratification and screening.