Background Current guidelines recommend consideration of germline genetic testing for patients with uterine serous carcinoma (USC) but real-world data are limited on completion rates of testing and pathogenic variant (PV) identification. This study aimed to evaluate the rate of genetic testing referral and completion in a cohort of patients with USC, determine the prevalence of clinically meaningful PVs found on testing and explore factors associated with genetics referral and testing completion.Methods We retrospectively examined the medical records of all individuals diagnosed with USC between 2019 and 2024 seen at a single academic cancer centre. Outcomes of interest included referral for germline genetic testing, completion of testing and testing results.Results Of 131 individuals included, 5 (3.8%) had prior genetic testing and only 45 (34.4%) were recommended to undergo genetic testing or referred to cancer genetics. Younger individuals and those with a personal history of cancer other than USC or family history of breast or ovarian cancer were more likely to be referred. Nine (26.5%) of 34 individuals who completed germline testing had a PV identified in a cancer-related gene, including BRCA1, BRCA2, BRIP1, CHEK2, MSH6, PMS2 and ATM. Only a personal history of cancer other than USC was independently associated with the discovery of a PV on germline genetic testing. In those without a prior personal history of cancer, the PV prevalence was 5.6%.Conclusions Given the high prevalence of PVs in this population, germline genetic testing for all patients diagnosed with USC can provide clinically meaningful benefit but is currently underused in practice.

ImportanceEnhanced breast cancer screening with magnetic resonance imaging (MRI) is recommended to women with elevated risk of breast cancer, yet uptake of screening remains unclear after genetic testing.ObjectiveTo evaluate uptake of MRI after genetic results disclosure and counseling.Design, Setting, and ParticipantsThis multicenter cohort study was conducted at the University of Southern California Norris Cancer Hospital, the Los Angeles General Medical Center, and the Stanford University Cancer Institute. Patients were recruited from July 1, 2014, through November 30, 2016. Following multiplex gene panel testing and genetic counseling, patients responded to surveys about breast MRI screening at 3, 6, 12, and 24 months and to a final survey between 3 and 4 years after counseling. Participants met standard clinical criteria for genetic testing or had a 2.5% or greater probability of inherited cancer susceptibility. Patients were categorized based on breast cancer risk from genetic testing results and Tyrer-Cuzick model-calculated risk as having (1) a BRCA or other high-risk pathogenic variant (PV), (2) a moderate-risk PV, (3) a higher lifetime breast cancer risk (≥20%), or (4) a lower lifetime breast cancer risk (<20%). Analysis was conducted from September 28 to November 9, 2023.InterventionsGenetic testing with a 25- or 28-gene panel, and pretest and posttest genetic counseling by a genetic counselor or an advanced practice genetics nurse practitioner, which included cancer-specific screening recommendations.Main Outcomes and MeasuresMRI screening adherence over time across risk groups was estimated using Cox proportional hazards regression modeling. Likelihood of screening adherence (odds ratios [ORs] with 95% CIs), controlling for potential confounders, was estimated using logistic regression.ResultsThis study included 638 patients, with a mean (SD) age of 50.7 (13.3) years at testing. There were 43 patients (6.7%) with a BRCA or other high-risk PV, 16 (2.5%) with a moderate-risk PV, 146 (22.9%) with higher lifetime breast cancer risk, and 433 (67.9%) with lower lifetime breast cancer risk. A total of 52 patients (8.2%) identified as Asian, 21 (3.3%) as Black, 271 (42.5%) as Hispanic, and 255 (40.0) as White. Compared with patients with lower lifetime breast cancer risk, patients with a BRCA or other high-risk PV and those with a moderate-risk PV were approximately 10 times (OR, 9.81 [95% CI, 4.05-23.86]; P < .001) and 4 times (OR, 4.12 [95% CI, 1.10-14.35]; P = .03) as likely to undergo MRI, respectively. Patients with a BRCA or other high-risk PV were nearly 16 times (OR, 15.81 [95% CI, 5.17-48.31]) as likely to report consistent yearly MRI screening compared with patients with lower lifetime risk.Conclusions and RelevanceIn this study, women with inherited PVs conferring increased breast cancer risk had higher and more consistent MRI uptake than women with lower estimated risk. These findings emphasize the importance of genetic cancer risk assessment for effective enhanced breast cancer screening.

e22603 Background: Constructing databases is crucial for answering clinical questions but is time-consuming and error-prone. Our institution has maintained a REDCap database of cancer genetics encounters since 2002, manually curated by research assistants. We explored automating some data entry using a HIPAA-compliant, commercially available large language model (LLM). Methods: We randomly selected 100 patients from our database since 2017; a board-certified oncologist reviewed each chart to establish a gold standard. We examined variable abstraction for (1) whether genetic testing was ordered, (2) whether genetic testing results were obtained, (3) whether a variant was identified and, if so, the (4) gene and (5) variant status (benign, uncertain significance, or pathogenic). For the LLM input, we provided every Epic note and letter from January 2017 to January 2025 from the Cancer Genetics group (n = 308) for the 100 patients. For patients with multiple notes, we took (1) concordant values from ≥ 2 notes or (2) a non-benign variant as the true LLM result. We made two API calls per note using Stanford Healthcare Secure GPT with OpenAI’s gpt-4o model. The code is available at https://github.com/MrJimb0/ASCO2025 . We calculated summary statistics for time, token use, accuracy, and sensitivity/specificity, with the oncologist chart review as the reference. Results: The LLM accurately categorized 88% of the 100 patients compared to 87% by research assistants in REDCap. LLM errors that occurred in more than one patient were from information being outside of the provided notes (n = 4), information being in an image never converted to text (n = 2), and incorrectly interpreting a familial variant as being the patients’ (n = 2). In contrast, errors in REDCap were from new results returning after the date the research assistant did data entry (n = 7) and typos (n = 5). 29% of the cohort had a pathogenic variant. The LLM had a sensitivity of 83% and specificity of 96% for pathogenic variant detection, compared to 76% and 100% for REDCap. The LLM processed an average of 9,801 input tokens and 372 output tokens per patient, processing each patient in approximately 24 seconds. For a research assistant, the average time was 6 minutes per patient. Assuming 2,500 patients in a year, typical for this clinic, the LLM would take 16.5 hours of work at around $72 compared to 250 hours, or $7,500 of effort, for a research assistant. Conclusions: Compared to abstraction by a research assistant, the LLM was quicker and had similar sensitivity and specificity for these five variables. We obtained these results without hyperparameter tuning, vectorization, note standardization, model retraining, or the development of a foundational model. These results suggest that commercial LLMs with limited prompt engineering and post-LLM processing can support chart review in cancer genetics, potentially reducing costs and improving the efficiency of database construction.

e17640 Background: There is emerging evidence for germline genetic contribution to cases of uterine serous carcinoma (USC). Cohort studies of individuals carrying BRCA1 or BRCA2 pathogenic variants have shown higher risks of USC than expected. Starting in 2023, the NCCN hereditary cancer testing guidelines state that genetic testing may be considered in patients with USC, but a lack of testing may be hindering our assessment of endometrial cancer genetic risks. This study aimed to study our institutional genetic testing rates and results over the past five years. Methods: The electronic medical records of a tertiary academic center were digitally searched to identify all patients diagnosed with USC and treated by the gynecologic oncology division between January 1, 2019 and December 31, 2023. Medical records were then manually abstracted to confirm inclusion and collect data on demographics, cancer pathology and staging, family history, genetic counseling referral and testing outcomes, and follow-up. Descriptive statistics were performed with comparison testing using Fisher’s exact tests. Results: 109 cases of USC were diagnosed and treated between 2019 and 2023, 35 (32%) stage I disease, 8 (7%) stage 2, 24 (22%) stage III, and 42 (39%) with stage IV by FIGO 2009 staging. 74 patients (67.9%) were not referred for genetic testing. 6 (5.5%) had prior genetic testing completed before their USC diagnosis (primarily due to another primary cancer diagnosis), with a pathogenic variant prevalence of 67.7% (4/6). Of 30 patients referred for genetic counseling after their USC diagnosis, only 21 (70%) ultimately underwent genetic testing with a pathogenic variant prevalence of 28.6% (6/21). Pathogenic variants identified spanned 9 potentially actionable genes (Table 1). Patients with a prior personal history of cancer were more likely to have a pathogenic variant identified on testing (56.3% vs. 9.1%, p=0.018). Patients with a personal or family history of cancer were more likely to be referred for genetic counseling (47.8% vs. 23.1%, p=0.34 and 40% vs. 20%, p=0.04, respectively). Conclusions: Genetic counseling and germline testing for patients diagnosed with uterine serous carcinoma has not been widely implemented. Of those tested at our single institution, there was a high prevalence of potentially actionable pathogenic variants, and wider testing will help us better quantify and address these genetic risks. Germline genetic testing results in patients diagnosed with uterine serous carcinoma between 2019 and 2023. N (total 27) % No pathogenic variant identified 17 63.0% BRCA2 2 7.4% BRCA1 1 3.7% APC 1 3.7% ATM 1 3.7% BRIP1 1 3.7% CHEK2 1 3.7% MSH2 1 3.7% MSH6 1 3.7% PMS2 1 3.7%

Importance:Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants. Objective:To describe gastric and breast cancer risk estimates for individuals with CDH1 variants. Design, Setting, and Participants:Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022. Main Outcomes and Measures:Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years. Results:A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%). Conclusions and Relevance:Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

We identified six patients from five families with a recurrent mutation: NM_000059.3 (BRCA2) exon 3 deletion. All families self-identified as Assyrian. Assyrians are an ethnoreligious population of ancient Mesopotamia, now mostly living in modern day Iraq, Syria, Turkey and Iran. They are historically a socially isolated population with intermarriage within their community, living as a religious and language minority in mostly Muslim countries. The probands of each family presented with a classic BRCA2-associated cancer including early-onset breast cancer, epithelial serous ovarian cancer, male breast cancer and/or high-grade prostate cancer, and family history that was also significant for BRCA2-associated cancer. BRCA2 exon 3 deletion is classified as pathogenic and has been previously described in the literature, but it has not been described as a founder mutation in a particular population. We characterise this recurrent BRCA2 pathogenic variant in five Assyrian families in a single centre cohort.

Abstract Introduction: A lack of access to genetic counseling for hereditary cancer risk in rural and underserved areas is well-documented and can exacerbate disparities in cancer risk reduction and early detection. Telehealth has the potential to bridge this gap, providing remote access to specialized care. The COVID-19 pandemic accelerated telehealth availability, allowing estimation of the causal effects of shifting to a model of virtual care delivery for genetic counseling services. Methods: The Stanford Cancer Genetic Counseling Clinic provided solely in-person care at two clinical sites (Palo Alto and San Jose, CA) until March 2020, and solely virtual care from April 2020 onward. We performed a regression discontinuity design, allowing outcomes comparison before and after the threshold of early 2020, to evaluate the impact of telehealth genetic counseling on access to care for patients living in areas of higher deprivation. The assignment variable (the exposure measured before versus after the threshold) was the three-month period during which the patients were seen, with the March-May 2020 quarter excluded because of disruption of care during the early COVID-19 pandemic. The primary endpoint was proportion of patients whose primary residence zip code had a state area deprivation index of at least 4. Secondary endpoints included driving distance to the primary clinic location in Palo Alto, CA, insurance type, race/ethnicity, and primary language. Results: The study included N=5,957 patients seen in the Stanford Cancer Genetics Program between January 2017 and February 2020, and N=9,469 patients seen between June 2020 and April 2024. The regression discontinuity analysis revealed a significant discontinuity at the threshold for telehealth in access for patients living in areas of higher deprivation, who accounted for 22% of patients seen just prior to telehealth implementation and 27% just after telehealth implementation, a proportional increase of 21% (p=0.006). Mean driving distance to Palo Alto, CA also increased, from 49 minutes just prior to the threshold to 56 minutes just after (p=0.003). There were no significant differences in insurance type, race/ethnicity, or primary language across the threshold. Conclusion: The implementation of telehealth services at the Stanford Cancer Genetic Counseling Clinic significantly improved access to genetic counseling for patients from areas with higher deprivation, as evidenced by a 21% increase in the proportion of such patients among those seen. These results quantify the effectiveness of telehealth in reducing geographical and socioeconomic barriers to specialized genetic counseling and testing services. Citation Format: Jennifer L. Caswell-Jin, Hao Tang, Mina Satoyoshi, Kerry Kingham, Allison W. Kurian. Improving access to genetic counseling and testing for underserved populations through telehealth [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C125.

The process of interpreting genetic variants, in which experts use all available evidence to determine whether an identified variant is associated with a current or future disease, is both scientific and nevertheless subjective. In this paper, we summarize the existing evidence that any given variant could be reclassified and that such a reclassification could lead to harm. Furthermore, the racial gap in genetic databases could lead to a higher likelihood of harm for non-white patients. We also review recent legal analyses indicating it is unlikely that an individual who sues for restitution would be successful, especially in the absence of evidence of lab negligence. We then propose a compensation program for medical genetic tests to ensure that individuals who experience demonstrable harm due to a variant reclassification can be made whole financially. We conclude by discussing outstanding questions that must be answered for such a program to be feasible.

Purpose: Multiplex gene panel testing (MGPT) is used to identify individuals with an inherited susceptibility to cancer. However, little is known about the uptake of screening and surveillance among patients after MGPT and genetic counseling. The purpose of this study was to measure the uptake of guideline-concordant breast cancer screening after genetic testing and counseling. Patients and Methods: 2,000 patients who met NCCN testing guidelines or had ≥2.5% probability of a pathogenic/likely pathogenic variant (PV) were recruited at three cancer genetics clinics (University of Southern California (USC) Norris Comprehensive Cancer Center, Los Angeles County + USC Medical Center, Stanford Cancer Institute) from July 2014 through November 2016. All patients had 25- or 28-gene MGPT and results were disclosed by a genetic counselor, who provided screening recommendations to patients based on their risk. Post-test surveys were administered at three months, six months, one year, two years, and three years. Results: 1,614/2,000 (80.7%) patients were female and 1,147/1,614 (71.7%) completed at least one survey regarding MRI screening for breast cancer over the three years of longitudinal follow-up. Of these, 94/1,147 (8.2%) patients tested positive for at least one PV in a breast cancer risk gene; 58/94 (61.7%) tested positive for PVs in a high-risk breast cancer gene (BRCA1/2 (n=53), CDH1, PALB2, TP53 (n=5)), and 34/94 (36.2%) of patients tested positive for a PV in a gene characterized as moderate-risk at the time of disclosure (CHEK2, ATM, NBN). MRIs were recommended to 43/58 (74.1%) patients with a high-risk breast cancer gene PV, 20/34 (58.8%) patients with a moderate-risk gene PV, and 171/1,053 (16.2%) patients without a breast cancer risk gene PV. Multivariate logistic regression models revealed that patients with a high-risk gene PV were more likely to undergo MRI screening within 3 months of receiving genetic test results (OR=6.54 95% CI [3.09 - 14.43], p< 0.001), within one year (OR=1.34 95% CI [1.18 - 1.52], p< 0.001), two years (OR=1.43 95% CI [1.24 – 1.65], p< 0.001), and three years (OR=1.44 95% CI [1.25 – 1.66], p< 0.001) when compared to patients without a PV. Patients with a moderate-risk PV were also more likely to have undergone MRI within 3 months of receiving genetic test results (OR=2.89 95% CI [1.05 - 7.81], p=0.036), within one year (OR=1.33 95% CI [1.10 - 1.62], p=0.004), two years (OR=1.31 95% CI [1.09 - 1.59], p=0.004), and three years (OR=1.44 95% CI [1.18 - 1.76], p< 0.001), compared to those without a PV (Table 1). Conclusions: After three years of longitudinal follow up of 2000 patients in this multicenter prospective cohort study, patients with a PV in a breast cancer susceptibility gene were more likely to undergo guideline concordant breast MRI compared to patients without a PV. Carriers of high-risk breast cancer gene PVs were over six times as likely to have undergone MRI compared to patients without PVs within the first three months after genetic results disclosure and counseling. These results demonstrate the effectiveness of MGPT and genetic counseling in guiding patients with PVs in breast cancer susceptibility genes to the appropriate adoption of guideline-concordant screening. Odds ratios of MRI screening in patients carrying PV in breast cancer risk genes. Odds in relation to patients who do not carry a PV High risk gene PV: BRCA1/2, CDH1, PALB2, TP53; Moderate Risk PV: CHEK2, ATM, NBN. Percent of patients having undergone an MRI at the specified time points High risk gene PV: BRCA1/2, CDH1, PALB2, TP53; Moderate Risk PV: CHEK2, ATM, NBN. Citation Format: Leah A. Naghi, Charite N. Ricker, Duveen Sturgeon, Julie Culver, Kerry Kingham, Rachel Hodan, Nicolette M. Chun, John Kidd, Joseph Bonner, Christine Hong, Meredith Mills, Sidney S. Lindsey, Kevin McDonnell, Uri Ladabaum, James M. Ford, Stephen Grube, Allison W. Kurian, Gregory E. Idos. Uptake of Breast Cancer MRI Screening in Patients After Multiplex Gene Panel Testing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-07.

PURPOSE:The aim of this study was to describe the clinical impact of commercial laboratories issuing conflicting classifications of genetic variants. METHODS:Results from 2000 patients undergoing a multigene hereditary cancer panel by a single laboratory were analyzed. Clinically significant discrepancies between the laboratory-provided test reports and other major commercial laboratories were identified, including differences between pathogenic/likely pathogenic and variant of uncertain significance (VUS) classifications, via review of ClinVar archives. For patients carrying a VUS, clinical documentation was assessed for evidence of provider awareness of the conflict. RESULTS:Fifty of 975 (5.1%) patients with non-negative results carried a variant with a clinically significant conflict, 19 with a pathogenic/likely pathogenic variant reported in APC or MUTYH, and 31 with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. Only 10 of 28 (36%) patients with a VUS with a clinically significant conflict had a documented discussion by a provider about the conflict. Discrepant counseling strategies were used for different patients with the same variant. Among patients with a CDKN2A variant or a monoallelic MUTYH variant, providers were significantly more likely to make recommendations based on the laboratory-reported classification. CONCLUSION:Our findings highlight the frequency of variant interpretation discrepancies and importance of clinician awareness. Guidance is needed on managing patients with discrepant variants to support accurate risk assessment.

AbstractBackgroundThere are limited data on the prevalence of Lynch syndrome (LS) in women with primary ovarian cancer with mismatch repair deficiency (MMR‐D) by immunohistochemistry (IHC).Materials and MethodsThree hundred and eight cases of primary ovarian, fallopian, and peritoneal cancer between January 2012 and December 2019 were evaluated for MMR‐D by IHC. The incidence of LS in this cohort was evaluated.ResultsMMR‐D by IHC was identified in 16 of 308 (5.2%) (95% CI: 3.2%–8.3%) primary ovarian‐related cancers. Most cases with MMR‐D were endometrioid (n = 11, 68.7%); (95% CI: 44.2%–86.1%). MSH2/MSH6 protein loss was detected in eight cases (50.0%); (95% CI: 28.0%–72.0%) and MLH1/PMS2 protein loss was detected in four cases (25.0%); (95% CI: 9.7%–50.0%). MSH6 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%) and PMS2 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%). All four cases with MLH1/PMS2 protein loss had MLH1 promotor hypermethylation. All 12 women with ovarian cancer suggestive of LS underwent germline testing and 8 (66.6%); (95% CI: 38.8%–86.5%) were confirmed to have LS.ConclusionsMost ovarian cancers with somatic MMR‐D were confirmed to have LS in this cohort. Germline testing for LS in addition to BRCA1/2 for all women with an epithelial ovarian cancer would be efficient and would approach 100% sensitivity for identifying Lynch syndrome. Utilization of a multigene panel should also be considered, given the additional non‐Lynch germline mutation identified in this cohort.

1549 Background: While germline pathogenic variants (PVs) in BRCA1/2 account for a large proportion of hereditary breast cancer (BC), PVs in PALB2, CHEK2 and ATM are increasingly detected. However, the phenotype and clinical features of invasive BC with these PVs have not been fully described. Methods: We identified patients with a PV or likely PV in PALB2, CHEK2 or ATM tested clinically at Stanford between 2014 - 2019 who provided informed consent to be included in a prospective cancer genetics registry. Data on baseline demographics, genetic testing history, and clinicopathologic features of diagnosed BC were collected. For patients with a subsequent diagnosis of metastatic BC, we calculated disease-free interval (DFI). Results: 130 patients met inclusion criteria for analysis: ATM (N=39), CHEK2 (N=58), PALB2 (N=33). Nearly all (98.5%) were women, with 2 male BC in ATM carriers. Non-Hispanic White ethnicity was most common in ATM (64.1%, 95% CI 48.4%-77.3%) and CHEK2 carriers (69.0%, 95% CI 56.1%-79.4%), but comprised only 39.4% (95% CI 24.7%-56.4%) in PALB2 carriers. Asian/Pacific Islander (24.2%, 95% CI 12.6%-41.3%) and Hispanic (30.3%, 95% CI 17.3%-47.5%) ethnicities were enriched among PALB2 mutation carriers. In total, 97.7% learned of their PV status only after a preceding diagnosis of BC and 43.1% were diagnosed with BC at age ≤ 45. Data regarding invasive BC subtypes, incidence of subsequent primary BC, and metastatic recurrence are listed below in the table. Additional data on stage, grade and sites of metastatic spread will be presented. Conclusions: We observed clinically important differences in the spectrum of BC subtypes among carriers of ATM, CHEK2 and PALB2 PVs, in addition to racial/ethnic differences with Asian/Pacific Islander and Hispanic ethnicity enriched among carriers of PALB2 PVs. [Table: see text]

Background Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate‐risk pathogenic variants (PVs). Methods Study participants (N = 1264) were counseled and tested with a 25‐ or 28‐gene panel and completed a 3‐month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA). Results The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non‐Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non–English‐speaking. The genetic test results were as follows: 7% had a high‐risk PV, 6% had a moderate‐risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of “never,” “rarely,” or only “sometimes” reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high‐ and moderate‐risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High‐ and moderate‐risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences. Conclusions In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds. Lay Summary Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate‐risk pathogenic variants (mutations) and among carriers of variants of uncertain significance. This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% “never,” “rarely,” or only “sometimes” reacted negatively to results. Somewhat higher uncertainty and distress were identified among carriers of high‐ and moderate‐risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result. Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results.

Purpose Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations. Patients and Methods This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics—University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute—who met testing guidelines or had a 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate). Results Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% v 41%; P < .001) to encourage their relatives to be tested. Conclusion In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results.

1525 Background: Guidelines recommend consideration of prophylactic surgery for patients with a germline pathogenic variant in some cancer predisposition genes. We assessed surgery utilization in a prospective, multi-institutional cohort study of MGPT. Methods: 2000 patients had MGPT and completed questionnaires at 3, 6, and 12 months. Patients reported surgical utilization and indication (treatment or prevention). Surgery utilization was assessed according to cancer history and MGPT test results: Positive, pathogenic variant; VUS, variant of uncertain significance; Negative, benign variants. Results: Overall, 12.9% (198/1537) of patients reported surgery after MGPT (median follow-up 13 months). Only 31.3% (62/198) of patients specified that their surgery was preventive. Preventive surgery utilization was significantly higher among patients who tested positive (n=30, 14.9%) compared to those testing negative (n=20, 2.3%, p<0.001) or VUS (n=12, 2.2%, p<0.001). Preventive surgery was very low among patients testing negative or VUS who had no personal history of cancer in the relevant organ (Table). For example, mastectomy was not reported among any patients testing negative or VUS who had no personal history of breast cancer (Table). Conclusions: More than one year after MGPT, prophylactic surgery use was low among patients with VUS or negative results, especially among those with no personal history of cancer at the relevant site. Surgery utilization. [Table: see text]