Case series examining somatic test results for patients with hereditary cancer syndromes associated with gastrointestinal cancer risk.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 680-680
Author(s):  
Kristen Pauley ◽  
Cathryn Koptiuch ◽  
Samantha Greenberg ◽  
Gammon Amanda ◽  
Christopher Nevala-Plagemann ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Treatment Options ◽  
Case Series ◽  
Parp Inhibitors ◽  
Cancer Genes ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Test Criteria ◽  
Uncertain Significance ◽  
Germline Testing

680 Background: Somatic tumor testing may identify germline pathogenic variants (PV) associated with cancer predisposition syndromes. Labs differ whether they offer somatic only or paired germline analysis. Methods used by somatic testing labs, even those that include germline analysis, differ from designated germline labs that have optimized the identification of germline PV. Methods: Chart reviews were performed for patients who had testing through both somatic and designated germline laboratories. Cases with discrepant results in which germline PV were not detected by the somatic laboratory are summarized. Results: Nine cases with discrepant results. Five had paired germline testing and 4 somatic testing only. All 9 patients met the criteria to undergo designated germline testing, either for Lynch syndrome (3) or BRCA1/2 testing (6), based on personal and/or family history. Designated germline testing identified 4 MLH1, 1 BRCA1, 2 ATM, 1 MUTYH and 1 RAD50 PV not reported by the somatic labs’ tumor or germline analysis; 2 MLH1 PV were called variants of uncertain significance by somatic testing but classified as PV by ClinVar and designated germline labs. Three PV identified by designated germline labs are targets for PARP inhibitors and resulted in different treatment options. Three of the MLH1 PV were identified in patients meeting Lynch Syndrome test criteria while 1 was identified in a patient meeting BRCA1/2 criteria. Among the 5 other patients meeting BRCA1/2 test criteria, 3 had PV in breast cancer genes (2 ATM, 1 BRCA1) and 2 had PV in other cancer genes ( MUTYH and RAD50) not reported by the somatic labs, highlighting the importance of panel testing. Conclusions: Methods used by somatic labs, regardless of inclusion of germline analysis, are not equivalent to those of designated germline labs. Overlooked germline PV may miss identification of hereditary syndromes and targeted therapy opportunities (e.g. Anti-PD1 immunotherapy, PARP inhibitors). Patients meeting criteria for genetic evaluation should be referred for designated germline testing regardless of somatic testing outcomes.

scholarly journals A scalable EHR-based approach for phenotype discovery and variant interpretation for hereditary cancer genes

2021 ◽  
Author(s):  
Chenjie Zeng ◽  
Lisa A Bastarache ◽  
Ran Tao ◽  
Eric Venner ◽  
Scott Hebbring ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Meta Analysis ◽  
Genetic Disorders ◽  
Genomic Medicine ◽  
Risk Scores ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Emerge Network ◽  
Uncertain Significance ◽  
Potential Pathogenicity

Knowledge of the clinical spectrum of rare genetic disorders helps in disease management and variant pathogenicity interpretation. Leveraging electronic health record (EHR)-linked genetic testing data from the eMERGE network, we determined the associations between a set of 23 hereditary cancer genes and 3017 phenotypes in 23544 individuals. This phenome-wide association study replicated 45% (184/406) of known gene-phenotype associations (P = 5.1 ×10-125). Meta-analysis with an independent EHR-derived cohort of 3242 patients confirmed 14 novel associations with phenotypes in the neoplastic, genitourinary, digestive, congenital, metabolic, mental and neurologic categories. Phenotype risk scores (PheRS) based on weighted aggregations of EHR phenotypes accurately predicted variant pathogenicity for at least 50% of pathogenic variants for 8/23 genes. We generated a catalog of PheRS for 7800 variants, including 5217 variants of uncertain significance, to provide empirical evidence of potential pathogenicity. This study highlights the potential of EHR data in genomic medicine.

ctDNA pathogenic variants (PVs) in homologous recombination repair (HRR) genes in patients with metastatic CRPC.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 138-138
Author(s):  
Ellen Jaeger ◽  
Elisa Marie Ledet ◽  
Marcus W. Moses ◽  
Charlotte Manogue ◽  
Brian E. Lewis ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Cancer Center ◽  
Small Subset ◽  
Published Data ◽  
Pathogenic Variants ◽  
Recombination Repair ◽  
Brca1 Brca2 ◽  
Allelic Fraction ◽  
Germline Testing

138 Background: HRR PVs can serve as predictive biomarkers and two PARP inhibitors are approved for metastasic CRPC (mCRPC) pts. Published data are predominantly focused on tissue-based assays, but obtaining tissue from mCRPC pts is problematic. In a large tissue based series (PROfound), 4047 mCRPC pts had tumor samples submitted for genomic testing but only 69% had interpretable results. No data were published from PROfound enumerating pts without available tissue to submit. Herein we assess frequency of PVs from selected HRR genes using a ctDNA assay. Methods: 292 mCRPC pts at Tulane Cancer Center were assessed for detectable HRR ctDNA changes using the Guardant 360 assay (which assesses the HRR genes BRCA1, BRCA2, and ATM). Results: 20/292 (6.8%) pts had a PV in ATM. However only 4/292 (1.4%) had > 1% mutant allelic fraction. Germline testing occurred in 18/20 of the ctDNA ATM PV pts and 0/18 had a germline PV. The PROfound series had 6.3% somatic PVs in ATM. 18/292 pts (6.2%) had a PV in BRCA2 and 12/292 (4.1%) had a mutant allelic fraction of > 1%. Germline testing was performed in 17/18 with BRCA2 ctDNA PVs and 9/17 had germline PVs. The PROfound series had 9.7% somatic BRCA2 PVs. BRCA1 PVs were detected in 6/292 (2.1%) pts and 3/292 (1%) had a mutant allelic fraction > 1%. 6/6 of the ctDNA PVs has germline testing and 1/6 had a BRCA1 PV. The PROfound series had 1.3% somatic PVs in BRCA1. Conclusions: Using ctDNA essay, it is feasible to measure PVs in only a small subset of HRR genes in mCRPC pts. These assays fail to detect deep deletions, a known and important mechanism of HRR gene loss. The ctDNA mutant allelic fractions are often low. The ability of ctDNA PVs using this assay to predict treatment effects are unknown.

Comparison of Somatic and Germline Variant Interpretation in Hereditary Cancer Genes

2019 ◽  
pp. 1-8
Author(s):  
Emily W. Moody ◽  
Jennie Vagher ◽  
Whitney Espinel ◽  
David Goldgar ◽  
Kelsi J. Hagerty ◽  
...  
Keyword(s):  
Health Care Providers ◽  
Hereditary Cancer ◽  
Clinical Test ◽  
Variant Interpretation ◽  
Test Results ◽  
Cancer Genes ◽  
Care Providers ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Brca1 Brca2

PURPOSE To compare the classification of genetic variants reported on tumor genomic profiling (TGP) reports with germline classifications on clinical test results and ClinVar. Results will help to inform germline testing discussions and decisions in patients with tumor variants in genes that are relevant to hereditary cancer risk. PATIENTS AND METHODS This study compared somatic and germline classifications of small nucleotide variants in the following genes: BRCA1, BRCA2, CHEK2, PALB2, ATM, MLH1, MSH2, MSH6, and PMS2. Somatic classifications were taken from reports from a single commercial TGP laboratory of tests ordered by providers at Huntsman Cancer Institute between March 2014 and June 2018. Somatic variant interpretations were compared with classifications from germline test results as well as with ClinVar interpretations. RESULTS Of the 623 variants identified on TGP, 353 had a definitive classification in ClinVar, and 103 were assayed with a germline test, with 66 of the variants tested observed in germline. Analysis of somatic variants of uncertain significance listed on TGP reports determined that 22% had a different interpretation compared with ClinVar and that 32% differed from the interpretation on a germline test result. Pathogenic variants on TGP test results were found to differ 13% and 5% of the time compared with ClinVar interpretations and germline test results, respectively. CONCLUSION These results suggest that TGP variants are often classified differently in a germline context. Differences may be due to different processes in variant interpretation between somatic and germline laboratories. These results are important for health care providers to consider when making decisions about additional testing for hereditary cancer risks.

Germline pathologic mutations and cancer family history in prostate cancer patients.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 378-378
Author(s):  
Marcus Marie Moses ◽  
Elisa Ledet ◽  
Emma M. Ernst ◽  
Patrick Cotogno ◽  
Joshua Schiff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Family History ◽  
San Francisco ◽  
Treatment Options ◽  
Distant Metastases ◽  
Cancer Center ◽  
Chi Square ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Uncertain Significance

378 Background: Prostate cancer (PCa) patients (pts) with metastases and/or strong family history (FH) of cancer (Ca) are at higher risk of a germline mutation. The identification of alterations in PCa pts may be important for risk stratification as well as personalizing treatment options. The goal of this study was characterization of FH and pathogenic variants (PV) detected in PCa pts, with both localized and metastatic disease. Methods: 300 PCa pts from Tulane Cancer Center underwent germline testing. 265 Caucasian (C) and 35 African-Americans (AA) were tested and met the NCCN criteria for testing and/or had distant metastases (mets). Germline genetic testing was done via commercial panels (30-80 genes) (Invitae. San Francisco, Ca). PCa pts had extensive FH screening. Clinical annotation included age at diagnosis (dx), race, and presence of mets at any time. Chi square tests were used to compare clinical correlates and PVs. Results: Of the 300 pts tested, 182 pts (60.6%) had mets and 118 (39.4%) did not. 41 pts (13.6%) had ≥ 1 germline pathogenic variant (PV) and 161 pts (53.6%) had ≥ 1 germline variant of uncertain significance (VUS). PVs were detected in BRCA2 (n = 10), MUTYH (n = 8), CHEK2 (n = 6), BRCA1 (n = 4), ATM (n = 4), TP53 (n = 3), PMS2 (n = 2), BLM (n = 2), MITF (n = 2), NBN (n = 1), and RAD51D (n = 1). MUTYH and MITF are not known to be linked to prostate cancer. There was no significant relationships in FH PCa and FH non-PCa in regard to likelihood of a PV (p = .86 and p = .18). Of the 300 pts tested, 136 pts (45.3%) had PCa FH, 131 pts (43.6%) had breast Ca FH, 61 pts (20.3%) had lung Ca FH, 61 pts (20.3%) had colon Ca FH, 37 pts (12.3%) had pancreatic Ca FH, and 32 pts (10.6%) had ovarian Ca FH. 45.6% of C men (n = 121) and 42.8% of AA men (n = 15) had PCa FH. Pts with a non-PCa FH (n = 255) were 1.37 times more likely to develop mets (p = .01168). The median age of dx were 61 for PV pts, 62 for VUS pts, and 61 for negative pts (non-significant). 21/182 pts with mets (11.5%) had a PV; 8/182 (4.4%) pts with mets had a BRCA2 PV. Conclusions: In metastatic patients, FH of prostate cancer alone cannot predict those with PV. The most common Cas observed in these pts were breast, lung, colon and pancreatic. A larger cohort is needed to fully characterize and understand the co-segregation of PCa with other Cas.

Large germline next generation (NGS) sequencing panel of uterine serous carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13106-e13106
Author(s):  
Ignacio Romero ◽  
Zaida Garcia-Casado ◽  
Raquel Lopez-Reig ◽  
Antonio Fernandez-Serra ◽  
Carmen Illueca ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Familial Cancer ◽  
Recessive Gene ◽  
Tumor Infiltrating Lymphocytes ◽  
Genetic Alterations ◽  
Serous Carcinoma ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Pathogenic Mutations ◽  
Uterine Serous Carcinoma

e13106 Background: Genetic predisposition to uterine serous carcinoma (USC) remains unclear and has been related to Lynch Syndrome (LS) and BRCA1/2 mutations. Wide NGS panels for this condition are starting to be implemented and data remain scarce. Methods: Consecutive USC were identified from a prospective endometrial cancer database (ECD) in a single institution. Clinical information including stage, follow-up, a three-generation pedigree, Microsatellite Instability (MSI) with 8 markers and the Mismatch Repair Protein (MMRPro) staining status, was retrieved from the ECD. Germline genetic testing was performed using a commercially available NGS panel including 80 familial cancer genes (Onco-GeneSGKit) on a MiSeq sequencer. Pathogenic or likely pathogenic variants were confirmed by Sanger sequencing. Results: Twenty-one women out of a total of 150 (14%) cases contained in the ECD were diagnosed with a USC. Median age was 65 (40-84 yo), median Body Mass Index of 26 (19-40), and histologically 18 were defined as pure and 3 as mixed USC. FIGO 2009 stages were I/II and III/IV in 42% and 58% of cases respectively. Adjuvant Chemotherapy (CT) was administered to 76%. MSI-High and MMRPro loss was described in 5%, 19% fulfilled Bethesda criteria, 23% had previous breast cancer and 5% personal Lynch related cancer history, 28% presented with pathological features of Lynch Syndrome such as dedifferentiation, Tumor Infiltrating Lymphocytes (14%), peritumoral lymphocytes or lower uterine location (14%). A median of 5 [range: 2-8] genetic alterations (pathogenic, variants of uncertain significance (VUS) and not described) per patient were observed, including 3 (14.3%) pathogenic mutations, 18 VUS and 43 not described. Among the three pathogenic mutations one was in MSH6 (p.Glu255Ter), another one in DKC1 (p.S280A) and the last one in the recessive gene MUTYH (p.Glu466del). VUS were detected in 57% of cases among 12 different genes: ATM (n = 3), AXIN2 (n = 2), BARD1 (N = 2), RAD50 (n = 2), RET (n = 2) and one case each of BMPR1A, BRIP1, CHEK2, MLH1, MSH6, SLX4 and TSC2. Conclusions: In our series 14% of USC harbored mutations in cancer predisposition genes.VUS are as high as 57% and represent a clinical challenge.

The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families

2019 ◽  
pp. 79-86 ◽  
Author(s):  
Robert Pilarski
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitors ◽  
Gleason Grade ◽  
Brca1 And Brca2 ◽  
Direct Evaluation ◽  
Panel Testing ◽  
Post Test ◽  
Uncertain Significance ◽  
Prostate Cancers

Beyond breast and ovarian cancers, mutations in the BRCA1 and BRCA2 genes increase risks for pancreatic and prostate cancers and contribute to the prevalence of these cancers. Mutations in a number of other genes have also been shown to increase the risk for these cancers as well. Genetic testing is playing an increasingly important role in the treatment of patients with pancreatic and prostate cancer and is now recommended for all patients with pancreatic or metastatic prostate cancer, as well as patients with high Gleason grade prostate cancer and a remarkable family history. Identification of an inherited mutation can direct evaluation of the patient for other cancer risks as well as identification and management of disease in at-risk relatives. Growing evidence suggests improved responses to PARP inhibitors and other therapies in patients with mutations in the BRCA and other DNA repair genes. Although more work must be done to clarify the prevalence and penetrance of mutations in genes other than BRCA1 and BRCA2 in patients with pancreatic and prostate cancer, in most cases, testing is now being done with a panel of multiple genes. Because of the complexities in panel testing and the increased likelihood of finding variants of uncertain significance, pre- and post-test genetic counseling are essential.

scholarly journals Interpretation of BRCA2 Splicing Variants: A Case Series of Challenging Variant Interpretations and the Importance of Functional RNA Analysis

2021 ◽  
Author(s):  
Paola Nix ◽  
Erin Mundt ◽  
Bradford Coffee ◽  
Elizabeth Goossen ◽  
Bryan M. Warf ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Case Series ◽  
Cancer History ◽  
Rna Analysis ◽  
Pathogenic Variants ◽  
Conflicting Evidence ◽  
Increased Risk ◽  
Splicing Variants ◽  
Uncertain Significance ◽  
In Silico Models

AbstractA substantial proportion of pathogenic variants associated with an increased risk of hereditary cancer are sequence variants affecting RNA splicing. The classification of these variants can be complex when both non-functional and functional transcripts are produced from the variant allele. We present four BRCA2 splice site variants with complex variant interpretations (BRCA2 c.68-3T>G, c.68-2A>G, c.425G>T, c.8331+2T>C). Evidence supporting a pathogenic classification is available for each variant, including in silico models, absence in population databases, and published functional data. However, comprehensive RNA analysis showed that some functional transcript may be produced by each variant. BRCA2 c.68-3T>G results in a partial splice defect. For BRCA2 c.68-2A>G and c.425G>T, aberrant splicing was shown to produce a potentially functional, in-frame transcript. BRCA2 c.8331+2T>C may utilize a functional GC donor in place of the wild-type GT donor. The severity of cancer history for carriers of these variants was also assessed using a history weighting algorithm and was not consistent with pathogenic controls (carriers of known pathogenic variants in BRCA2). Due to the conflicting evidence, our laboratory classifies these BRCA2 variants as variants of uncertain significance. This highlights the importance of evaluating new and existing evidence to ensure accurate variant classification and appropriate patient care.

Differences in the genomic landscape of advanced prostate cancer (aPC) patients (pts) with BRCA1 versus BRCA2 mutations as detected by machine learning analysis of the comprehensive genomic profile (CGP) of cell-free DNA (cfDNA).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 162-162
Author(s):  
Raquel Reisinger ◽  
Sergiusz Wesolowski ◽  
Umang Swami ◽  
Pedro C. Barata ◽  
Edgar Javier Hernandez ◽  
...  
Keyword(s):  
Machine Learning ◽  
Bayesian Network ◽  
Graphical Models ◽  
Parp Inhibitors ◽  
Cancer Genes ◽  
Castration Resistance ◽  
Exact Test ◽  
Pathogenic Variants ◽  
Brca 1 ◽  
Brca2 Mutations

162 Background: PARP inhibitors (PARPi) provide significant clinical benefit for men with aPC with BRCA 1 and BRCA 2 mutations. However, in clinical trials, pts with BRCA1 mutations appeared to derive less benefit than pts with BRCA2 (De Bono et al., 2020). Probabilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that PGMs can reveal variants in BRCA1 and 2 that co-segregate with other known pathogenic variants and may explain the difference in response to PARPi therapy. Methods: Multilevel gene interdependencies between BRCA1 or BRCA2 were assessed using a Bayesian Network (BN) machine learning approach and Fisher’s exact test. CGP was performed by a validated cfDNA NGS panel that sequenced 74 clinically relevant cancer genes (Guardant360, Redwood City, CA). Only variants of known significance and those of unknown significance with a pathogenic REVEL score were included in the analysis. Results: Of 4671 men with aPC undergoing cfDNA CGP, 1248 men with somatic mutations in BRCA1, BRCA2, ATM, or combinations of the three were included in the analysis. The Bayesian network analysis demonstrated positive interdependencies between pathogenic variants in BRCA1 and 7 other genes. A positive interdependency between BRCA2 and 2 genes was present (table). ATM displayed negative interdependency with both BRCA 1 and 2. Conclusions: Our results demonstrate a decreased association of BRCA2 versus BRCA1 with known or predicted pathogenic variants at other loci. This may explain increased sensitivity of aPC with BRCA2 mutations to PARPi due to fewer concurrent resistance pathways. For example, alteration of ERBB2, which segregates strongly with BRCA1, is known to induce tumor progression and invasion in aPC and is associated with castration-resistance. These hypothesis-generating data reveal differential genomic signatures associated with BRCA1 as compared to BRCA2 and may inform development of future combinatorial treatment regimens for these pts. [Table: see text]

scholarly journals Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1007 ◽  
Author(s):  
Lorenza Pastorino ◽  
Virginia Andreotti ◽  
Bruna Dalmasso ◽  
Irene Vanni ◽  
Giulia Ciccarese ◽  
...  
Keyword(s):  
Rare Variants ◽  
Diagnostic Yield ◽  
Susceptibility Genes ◽  
Gene Panel ◽  
Missing Heritability ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Novel Variants ◽  
Uncertain Significance

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

scholarly journals Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk

2019 ◽  
pp. 1-12 ◽  
Author(s):  
Gregory E. Idos ◽  
Allison W. Kurian ◽  
Charité Ricker ◽  
Duveen Sturgeon ◽  
Julie O. Culver ◽  
...  
Keyword(s):  
Response Rate ◽  
Diagnostic Yield ◽  
Prophylactic Surgery ◽  
University Of Southern California ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Uncertain Significance ◽  
Multicenter Prospective Cohort Study ◽  
Multicenter Prospective Cohort

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.

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