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It is well recognised that medical training globally and at all levels lacks sufficient incorporation of genetics and genomics education to keep up with the rapid advances and growing application of genomics to clinical care. However, the best strategy to implement these desired changes into postgraduate medical training and engage learners is still unclear. We developed a novel elective rotation in ‘Genomic Medicine and Undiagnosed Diseases’ for categorical Internal Medicine Residents to address this educational gap and serve as an adaptable model for training that can be applied broadly across different specialties and at other institutions. Key curriculum goals achieved include increased understanding about genetic testing modalities and tools available for diagnosis and risk analysis, the role of genetics-trained allied health professionals, and indications and limitations of genetic and genomic testing in both rare and common conditions.

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., Multigene panel tests for hereditary cancer have become widespread despite concerns that carriers of moderate‐risk pathogenic variants or uncertain variants could have adverse psychological reactions. This large cohort study of patients undergoing panel testing has found that the psychological response is favorable, regardless of genetic test results.

Research on the communication of genetic test results has focused predominately on non-Hispanic White (NHW) mutation-positive families with high-risk hereditary cancer conditions. Little is known about this process for racially and ethnically diverse individuals or for those with mutations in moderate risk genes. The communication behaviors of study participants who carry a gene mutation were analyzed 3 months after disclosure of genetic test results. Participants were queried about communication of their results, as part of a prospective study of multi-gene panel genetic testing. The responses of particpants who tested positive were analyzed by race/ethnicity and by level of cancer risk (high vs. moderate). Of the 216 mutation-positive study participants, 136 (63%) responded. Self-reported race/ethnicity was 46% NHW, 41% Hispanic, 10% Asian, and 2% Black. The majority (99.0%, n = 135) had shared their results with someone and 96% had told a family member (n = 130). Hispanic respondents were less likely to have told a healthcare provider about their results than NHW (29% vs. 68%, p < .0001). Asian respondents were less likely than NHW to encourage family members to undergo testing (OR = 0.1, p = .03); but Asian family members were more likely to undergo testing (OR = 8.0, p = .03). There were no differences in communication between those with a mutation in a high- or moderate-risk gene. Three months post genetic testing, communication of results was very high; 30% reported a family member underwent genetic testing. Further studies are needed to better understand the communication process in individuals from diverse racial/ethnic backgrounds.

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

PurposeWe examined racial/ethnic differences in the usage and results of germ-line multiple-gene sequencing (MGS) panels to evaluate hereditary cancer risk.MethodsWe collected genetic testing results and clinical information from 1,483 patients who underwent MGS at Stanford University between 1 January 2013 and 31 December 2015.ResultsAsians and Hispanics presented for MGS at younger ages than whites (48 and 47 vs. 55; P = 5E-16 and 5E-14). Across all panels, the rate of pathogenic variants (15%) did not differ significantly between racial groups. Rates by gene did differ: in particular, a higher percentage of whites than nonwhites carried pathogenic CHEK2 variants (3.8% vs. 1.0%; P = 0.002). The rate of a variant of uncertain significance (VUS) result was higher in nonwhites than whites (36% vs. 27%; P = 2E-4). The probability of a VUS increased with increasing number of genes tested; this effect was more pronounced for nonwhites than for whites (1.1% absolute difference in VUS rates testing BRCA1/2 vs. 8% testing 13 genes vs. 14% testing 28 genes), worsening the disparity.ConclusionIn this diverse cohort undergoing MGS testing, pathogenic variant rates were similar between racial/ethnic groups. By contrast, VUS results were more frequent among nonwhites, with potential significance for the impact of MGS testing by race/ethnicity.

An 8-year-old male with lymphoblastic lymphoma was noted to have multiple café-au-lait macules and possible Lisch nodules. Work-up revealed the child as compound heterozygous for mutations in the DNA mismatch repair gene, MSH6. This case emphasizes many clinical issues regarding individuals with biallelic mismatch repair mutations, a rare and easily missed hereditary predisposition to childhood cancer. The issues include the need for high clinical suspicion based on skin examination findings and family history, the phenotypic similarity to neurofibromatosis type 1 with possibility of misdiagnosis, the high risk for subsequent malignances, and the need for further research of possible treatment resistance.

Background: Multiple-gene germline sequencing panels are increasingly used to evaluate hereditary cancer risk. However, little is known about the results of such testing in racially/ethnically diverse populations. Methods: Patients who presented to the Stanford University Clinical Cancer Genetics Program from 1/1/2013 to 12/31/2015 and underwent multiple-gene panel testing were included in the cohort (N=1,483). Information on demographics, personal and family history of cancer, and tumor characteristics was collected at time of clinic visit. Odds ratios and 95% confidence intervals were calculated for mutation status by different patient and tumor characteristics, including race/ethnicity. Results were compared using the chi-square test and considered significant if P Results: Most patients (92%) were female. Patients were 51% Non-Hispanic White (NHW), 19% Asian, 14% Hispanic, 10% Ashkenazi Jewish, 5% other, and 1% unknown. Eighty-nine genes were tested in at least one patient; panel size ranged from six to 62 genes, with a median of 25 genes. The frequency of pathogenic or likely pathogenic mutations was 15% for any panel-tested gene, 5.5% for BRCA1/2, and 5.3% for other breast cancer-associated genes; mutation frequencies were similar between NHW, Asian, Hispanic, and Ashkenazi Jewish patients. Variables significantly associated with the carriage of a pathogenic BRCA1/2 mutation included personal or family history of ovarian cancer and personal history of triple-negative breast cancer (TNBC). No variable was significantly associated with the presence of a pathogenic mutation in the other breast cancer genes. The odds ratios for carrying a BRCA1/2 mutation with personal history of ovarian cancer (4.1 [2.2-7.3]), family history of ovarian cancer (3.1 [1.9-4.9]), and TNBC relative to other breast cancer subtypes (6.0 [2.9-12.4]) did not differ significantly between NHWs and non-Whites. The frequency of variants of unknown significance (VUS) in any panel-tested gene was higher in non-Whites (36%) than in NHWs (27%) (P=2E-4), with the highest odds ratio relative to NHWs among Asians (2.0 [1.5-2.7], vs 1.3 [0.9-1.7] among Hispanics and 1.2 [0.8-1.7] among Ashkenazi Jews). The odds ratio of finding a VUS for non-Whites compared to NHWs was similar for any panel (1.5 [1.2-1.9]), for BRCA1/2 (1.3 [0.8-2.3]), and for other known breast cancer-associated genes (1.5 [1.1-1.9]). Conclusions: In this diverse cohort tested for hereditary cancer risk with multiple-gene panels, frequencies of pathogenic mutations were similar between racial/ethnic groups. By contrast, frequencies of VUS were significantly higher among non-Whites compared to NHWs. This higher VUS rate renders multiple-gene panel testing less informative for non-White patients. Efforts toward VUS re-classification, particular among non-Whites, are urgently needed to address this genetic information disparity. Citation Format: Caswell-Jin* JL, Gupta* T, Hall E, Petrovchich IM, Mills MA, Kingham KE, Koff R, Chun NM, Levonian P, Lebensohn AP, Ford JM, Kurian AW. Multiple-gene panel testing for hereditary cancer risk reveals a racial/ethnic disparity in genetic information [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD8-06.

e17583 Background: NCCN provides guidelines for breast cancer genetic risk assessment and testing. Measuring compliance with NCCN Guidelines (NG) can identify quality gaps. Methods: After IRB approval, a retrospective review of a prospective database of breast cancer patients was conducted to measure compliance with NG for genetic counseling and BRCA testing. Entry criteria were breast cancer patients with diagnosis and treatment at our center, during the 3 year period ending 12/31/11. Genetic counselors (GC) used NG and BRCAPRO modeling in all patients. Surgeon and GC pedigree analyses were compared. A change to the history was significant if the GC identified information that led to increased or decreased cases of breast or ovarian ca. Results: Surgeons constructed pedigrees in 675 breast cancer patients and referred 42% (286/675) to the GC. The decision to refer was NCCN compliant in 671/675 (99%). The GC corrected the pedigree in 14% (39/286); nearly all due to the GC identifying extra breast or ovarian cancers. The mean BRCAPRO probability in referred patients was 7.2%. Fifty-nine percent (170/286) of patients seen by the GC received a recommendation for BRCA testing. The NG compliance rate for testing was 98% (170/174). Of 174 BRCA tests offered to patients, 74% (128/174) underwent testing. In tested patients, there were 4% BRCA1+, 5% BRCA 2+, and 1% uncertain variants. Total patient charges for 128 tests were $696,000 ($4000/test). If the threshold for testing was BRCAPRO > 5% or >10%, then 69 ($276,000) and 45($180,000) (p