Cancer Genetics最新文献

{"title":"9. Best practices for testing and reporting of FISH studies in multiple myeloma: Recommendations from the CGC working group","authors":"Xinyan Lu ,&nbsp;Erica F. Andersen ,&nbsp;Rahul Banerjee ,&nbsp;Celeste C. Eno ,&nbsp;Patrick R. Gonzales ,&nbsp;Angela M. Lager ,&nbsp;Patricia M. Miron ,&nbsp;Trevor Pugh ,&nbsp;Fabiola Quintero-Rivera ,&nbsp;Virginia C. Thurston ,&nbsp;Daynna J. Wolff ,&nbsp;Jian Zhao ,&nbsp;Linda B. Baughn","doi":"10.1016/j.cancergen.2024.08.011","DOIUrl":"10.1016/j.cancergen.2024.08.011","url":null,"abstract":"<div><h3>Purpose</h3><div>Multiple myeloma (MM) remains an incurable plasma cell malignancy with recurrent primary and secondary cytogenetic abnormalities having prognostic and therapeutic implications. Fluorescence in situ hybridization (FISH) is the gold-standard assay to detect these genetic abnormalities. However, FISH testing for MM is heterogeneous among clinical laboratories, with differences in plasma cell isolation, FISH panel design, and reporting practices.</div></div><div><h3>Methods</h3><div>The CGC Plasma Cell Neoplasm workgroup conducted a survey targeting the international MM clinician community on utilization of FISH and result reporting/interpretation.</div></div><div><h3>Results</h3><div>There were 102 survey responses representing 14 countries. Most (74%) MM clinicians utilize their own in-house FISH testing service with 81% reporting plasma cell enrichment was performed by their lab. 90% of respondents desired FISH at diagnosis, 72% during disease progression and 40% for treatment/response assessment. The most-requested FISH probes included: TP53 (99%), t(4;14) (92%), 1q gain/amplification (91%), t(14;16) (90%), t(11;14) (85%), t(14;20) (76%), 1p deletion (67%), while FISH for ploidy status, deletion 13q/-13, t(6;14), MYC rearrangement, and other rare IG rearrangements were ranked lower in importance (10-50%). About 40% of respondents were dissatisfied with clarity, summary, and interpretation of FISH reports. When challenged to interpret a FISH report, only 2% of responders interpreted results correctly and the majority were either unsure or misinterpreted the report.</div></div><div><h3>Conclusion</h3><div>Our study showed that significant improvements are needed by clinical lab directors in MM FISH report clarity to benefit both the clinician and patient. We propose standardization of best MM FISH practices and reporting.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Pages S3-S4"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"75. Copy number variation heterogeneity as the measure for biological consistency in hierarchical cancer classifications","authors":"Ziying Yang,&nbsp;Paula Carrio-Cordo,&nbsp;Michael Baudis","doi":"10.1016/j.cancergen.2024.08.077","DOIUrl":"10.1016/j.cancergen.2024.08.077","url":null,"abstract":"<div><div>Cancers are heterogeneous diseases with unifying features of abnormal and consuming cell growth, where the deregulation of normal cellular functions is initiated by the accumulation of genomic mutations in cells of - potentially - any organ. At diagnosis malignant tumors present with patterns of somatic genome variants on diverse levels of heterogeneity. Among the different types of genomic alterations, copy number variants (CNV) represent a distinct, near-ubiquitous class of structural variants. Cancer classifications such as the National Cancer Institute Thesaurus (NCIt) provide large sets of hierarchical cancer classification vocabularies and promote data interoperability and ontology-driven computational analysis.</div><div>However, high heterogeneity in cellular phenotypes and dynamic plasticity of tumor microenvironments make tumor categorization a demanding and complicated task with the need to balance between categorical classifications and individual, 'personalized' feature definitions. To find out how categorical classifications reflect biological facts, we conducted a meta-analysis of inter-sample genomic heterogeneity at different levels of the classification hierarchies based on genome-spanning CNV profiles from 97,142 individual samples across 512 hierarchical cancer entities in the progenetix database. The use of a large data set of individual cancer samples allows for a greater exploration of genomic tumor heterogeneity between and inside given diagnostic concepts. With this study, we applied hierarchical clustering to quantify the heterogeneity among cancer entities through a refined measure of hamming dissimilarity based on CNV events. The results point out common/specific CNV patterns and potential subtypes of cancer entities, which will help in the improvement of patient stratification and current cancer classification.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S24"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2. Diagnostic next generation sequencing to detect MYD88 L265P in lymphoplasmacytic lymphoma compared to ddPCR","authors":"Lauren M. Wainman ,&nbsp;Guohong Huang ,&nbsp;Donald C. Green ,&nbsp;Eric Y. Loo ,&nbsp;Prabhjot Kaur ,&nbsp;Parth Shah ,&nbsp;Jeremiah Karrs","doi":"10.1016/j.cancergen.2024.08.004","DOIUrl":"10.1016/j.cancergen.2024.08.004","url":null,"abstract":"<div><div>Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration of lymphoplasmacytic cells. Studies have identified <em>MYD88</em> L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas (e.g. marginal zone lymphoma, chronic lymphocytic leukemia). However, detection rates for this mutation have varied depending on the analytic methodology, with data suggesting that routine Next Generation Sequencing (NGS) does not demonstrate the required sensitivity to reliably detect <em>MYD88</em> L265P. NGS has become a work-horse of the modern genetic laboratory by basketing multiple single-gene assays into one multiplexed assay. In several routine cases, visual observation using IGV demonstrated <em>MYD88</em> L265P variants in cases of suspected LPL with low tumor content. To study this, we performed droplet digital PCR (ddPCR) and our routine NGS for <em>MYD88</em> L265P in a cohort of 35 cases of lymphoid neoplasms (25 LPL, 6 CLL, 4 negative bone marrow cases). Our standard NGS method achieved an average depth of ∼535 reads across this region. We utilized manual review and BAMtools to assess <em>MYD88</em> L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.3% variant allele frequency (VAF) with 10ng DNA input. <em>MYD88</em> L265P VAF detection by NGS and ddPCR was comparable down to 0.5% VAF (R²=0.968). Setting an appropriate threshold for detection based on ddPCR results resulted in zero NGS false positives. This study demonstrates that NGS can be a sensitive and reliable method for detection of <em>MYD88</em> L265P with adequate coverage and specific assessment parameters.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S1"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"59. What the TERT? - A telomerase reverse transcriptase case study","authors":"Yeshmira Moodley,&nbsp;Longqian Yang,&nbsp;Bronwyn Neumann,&nbsp;Amanda Dixon-McIver","doi":"10.1016/j.cancergen.2024.08.061","DOIUrl":"10.1016/j.cancergen.2024.08.061","url":null,"abstract":"<div><div>Telomerase reverse transcriptase is a catalytic subunit of the telomerase protein that is involved in the maintenance of genomic stability. <em>TERT</em> aberrations are important biomarkers in the diagnosis, prognosis, and treatment of many human cancers. The <em>TERT</em> promoter has proven to be a difficult region of testing amongst a variety of currently available technologies.</div><div><em>TERT</em> promoter mutation analysis was performed on brain tissue of a 62-year old male meningioma patient using MALDI-TOF (Agena Bioscience MassARRAY platform) and detected a low frequency <em>TERT</em> mutation. The pathologist questioned the result and sent some of the sample for additional testing to 2 different referral laboratories - one aliquot was sent for Pyrosequencing and the other for NGS - both with a higher limit of detection than MALDI-TOF. Neither methodology detected a <em>TERT</em> mutation. On the basis of these result the diagnosis was changed.</div><div>Certain of our <em>TERT</em> mutation, an aliquot of the remaining extracted DNA was sent for digital droplet PCR (ddPCR) which has the same limit of detection as our MALDI-TOF platform. A <em>TERT</em> mutation was confirmed.</div><div>This case highlights the challenges in <em>TERT</em> promoter mutation analysis as well as the significance of confirmatory testing. The importance of confirming results using platforms with an appropriate limit of detection is paramount in reducing under-reporting of low level mutations of clinical significance.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S19"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"66. Prognostic impact of genomic testing results in patients undergoing transplantation for myelofibrosis","authors":"Xiaoyu Qu ,&nbsp;Emily Stevens ,&nbsp;Matt Fitzgibbon ,&nbsp;Lan Beppu ,&nbsp;Tim M. Monahan ,&nbsp;Cecilia C.S. Yeung ,&nbsp;Derek L. Stirewalt ,&nbsp;David Wu ,&nbsp;Jerald Radich ,&nbsp;H. Joachim Deeg ,&nbsp;Min Fang","doi":"10.1016/j.cancergen.2024.08.068","DOIUrl":"10.1016/j.cancergen.2024.08.068","url":null,"abstract":"<div><div>Despite its known superior detection rate for chromosomal anomalies compared to karyotype and FISH studies, Chromosome Genomic Array Testing (CGAT) is not used as a routine clinical test for myelofibrosis. We investigated the prognostic significance of CGAT and mutation results by NGS in myelofibrosis patients who underwent hematopoietic cell transplantation between 2000 and 2017 at our center (n=44). CGAT was done in a CLIA lab using CytoScanHD (ThermoFisher). NGS was performed either in a CLIA lab using UW Heme Gene Panel by NGS (n=9) or retrospectively at a research lab using TruSight myeloid panel (Illumina, n=35). Twenty-four patients (55%) had abnormal CGAT results. In 18 patients (41%), CGAT uniquely demonstrated cnLOH, with 9p cnLOH being the most frequent (n=8, 18%). Thirty-five patients had myeloproliferative neoplasm (MPN) driver mutations: 17 (39%) <em>JAK2</em> pV617F, 16 (36%) <em>CALR</em> exon 9 mutation, and two <em>MPL</em> pW515 (5%). With a median of 91 (range 2-258) months of follow-up, event-free survival (EFS; event referring to relapse) was 59%, and overall survival (OS) was 68%. Abnormal CGAT results (n=24, P=0.03), <em>U2AF1</em> mutation (n=5, P=0.028) and 1q gain (n=3, P=0.009) were associated with worse EFS. The genetic aberrations had no significant effect on OS in this cohort. <em>ASXL1</em> mutations (n=14) appeared to associate with a later onset of chronic graft-versus-host-disease (P=0.03). In conclusion, assessments by both CGAT and NGS pre-transplantation provide valuable outcome information and may be considered as routine clinical testing for myelofibrosis</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S21"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"34. Identifying challenges in variant normalization","authors":"Anastasia Bratulin ,&nbsp;Wesley A. Goar ,&nbsp;Kori Kuzma ,&nbsp;Lawrence Babb ,&nbsp;Kyle Ferriter ,&nbsp;Terry O'Neill ,&nbsp;Austin A. Antoniou ,&nbsp;Jeremy A. Arbesfeld ,&nbsp;Daniel Puthawala ,&nbsp;James S. Stevenson ,&nbsp;Jiachen Liu ,&nbsp;Xuelu Liu ,&nbsp;Brian Walsh ,&nbsp;William C. Ray ,&nbsp;Savanna Funk ,&nbsp;Bimal P. Chaudhari ,&nbsp;Heidi L. Rehm","doi":"10.1016/j.cancergen.2024.08.036","DOIUrl":"10.1016/j.cancergen.2024.08.036","url":null,"abstract":"<div><div>Genomic medicine relies on collecting information from multiple sources to make optimal therapeutic and diagnostic decisions for the patient. However, integration of this information, at the time of variant interpretation, is a major bottleneck. Challenges including inconsistent formats (e.g. HGVS and SPDI), and variant contexts (genome and proteome), increase the time and effort required to formulate and communicate a complete variant interpretation. To more clearly understand inter-resource differences in variant representation, variants from the Clinical Interpretations of Variants in Cancer (CIViC), Molecular Oncology Almanac (MOAlmanac), and ClinVar were evaluated using a normalization protocol. Of the variants in the knowledgebases, ∼53% of the CIViC, ∼42% of the MOAlmanac, and ∼99% of ClinVar variants were successfully normalized. We categorically assessed remaining variants for which normalization methods are still needed, and analyzed these for clinical impact. Gene fusion (e.g. 'ALK G1202R') and region-defined variant categories (e.g. '3′ UTR Mutations') respectively constitute 16% and 10% of all the variants that were not normalized, and were found to hold the greatest potential clinical impact. Additionally, fusion variants are responsible for ∼25% of all of the evidence items associated with not normalized variants from CIViC and MOAlmanac, illustrating the weight that fusion variants carry in the overall group. The Variation Normalizer is an open-source toolkit and is available for use with independent data sets to facilitate precise matching of evidence from knowledgebases to genomic variant data.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S11"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"43. Challenges of classifying variants associated with disorders of somatic mosaicism and guideline creation","authors":"Alexa Dickson,&nbsp;Kevin Bowling,&nbsp;Fernando Zazueta,&nbsp;Yang Cao","doi":"10.1016/j.cancergen.2024.08.045","DOIUrl":"10.1016/j.cancergen.2024.08.045","url":null,"abstract":"<div><div>Disorders of somatic mosaicism (DoSM) constitute rare genetic disorders characterized by post-zygotic events leading to segmental distribution of disease. The early presentation of associated phenotypes often mimics germline diseases, complicating molecular diagnosis. Additionally, current guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) focus specifically on germline and cancer variants, complicating the interpretation of DoSM-associated somatic variation. The ClinGen Brain Malformation Expert Panel guidelines have created valuable updates to account for brain-specific disorders of somatic mosaicism, but their applicability to the diverse DoSM presentations is limited. At Washington University School of Medicine, we have identified shortcomings in applying ACMG/AMP germline guidelines to DoSM variants, prompting the development of DoSM-specific variant interpretation guidelines. Leveraging our laboratory's extensive experience in somatic variation interpretation, we have developed DoSM guidelines that are applicable across genes and clinical contexts pertinent to non-cancerous somatic testing. These guidelines address the critical need for accurate somatic variant interpretation in DoSM, where treatment advances hinge on understanding the overlap between somatic variants in DoSM and tumors. This comprehensive framework addresses the gap in existing guidelines, offering an iinvaluable resource for clinical laboratories engaged in non-cancerous somatic testing and advancing precision medicine for patients with DoSM. We will present the developed guidelines, discuss challenges specific to DoSM and criteria development, and interesting cases studies where DoSM-specific guidelines were critical to accurate diagnosis.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S14"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"62. Characterization of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with KMT2A amplification","authors":"John O'Shea,&nbsp;Jian Zhao,&nbsp;Erica Andersen,&nbsp;Bo Hong","doi":"10.1016/j.cancergen.2024.08.064","DOIUrl":"10.1016/j.cancergen.2024.08.064","url":null,"abstract":"<div><div><em>KMT2A</em> amplification is a rare high risk cytogenetic abnormality in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which has been associated with complex karyotype, resistance to chemotherapy and higher frequency in elderly patients. Comprehensive elucidation of cytogenetic signatures in AML/MDS with <em>KMT2A</em> amplification, the subsequent clinical impact, as well as accompanying gene mutation profile would be beneficial for stratified patient care.</div><div>Herein, we present karyotyping/fluorescence in situ hybridization (FISH) data on 42 AML/MDS patients with <em>KMT2A</em> amplification, along with next generation sequencing (NGS) results and prognostic information in a subset of patients. The median age at diagnosis was 70 years. The male to female ratio was 1.8 (27:15). The median survival was 45 days. <em>KMT2A</em> amplification was identified by FISH. Chromosome analysis showed complex karyotype in all cases analyzed (n=38). The structural mechanisms associated with <em>KMT2A</em> amplification included homogeneously staining region (n=27), double minutes (n=6) and ring chromosome 11 (n=8). Deletions of 5q (64%) and 17p (62%) were the most common concurrent cytogenetic findings. Additional major concurrent cytogenetic abnormalities included loss of 7q (31%) and gain of chromosome 8 (29%). NGS results were available for 14 cases and <em>TP53</em> mutation was the most common alteration (n=12). Other mutations were detected in <em>TET2</em> (n=2), <em>NSD1</em> (n=2), <em>SAMD9L</em> (n=2), <em>DNMT3A</em> (n=1), <em>U2AF2</em> (n=1), <em>FLT3</em> (TKD, n=1), <em>NOTCH1</em> (n=1) and <em>SMC3</em> (n=1).</div><div>AML/MDS with <em>KMT2A</em> amplification is associated with poor outcome and specific concurrent cytogenetic and molecular abnormalities. Documenting additional data is valuable for improving the treatment landscape in these myeloid neoplasms.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S20"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"39. Modifying cancer variant interpretation guidelines for the curation of histone H3 variants: The 'next step' of the Cl","authors":"Laveniya Satgunaseelan ,&nbsp;Somak Roy ,&nbsp;Shivani Golem ,&nbsp;Jianling Ji ,&nbsp;Yassmine Akkari ,&nbsp;Elizabeth Spiteri ,&nbsp;Arpad Danos ,&nbsp;Wan-Hsin Lin ,&nbsp;Cameron Grisdale ,&nbsp;Obi Griffith ,&nbsp;Malachi Griffith ,&nbsp;Jason Saliba ,&nbsp;David Meredith","doi":"10.1016/j.cancergen.2024.08.041","DOIUrl":"10.1016/j.cancergen.2024.08.041","url":null,"abstract":"<div><div>Histone H3 variants pose numerous challenges for curation due to varied nomenclature for their isoforms and encoding genes. These are further compounded by the tumor-specific settings in which histone H3 variants occur. Therefore, the Histone H3 SC-VCEP aimed to adapt and modify the ClinGen/CGC/VICC Oncogenicity SOP and AMP/ASCO/CAP guidelines for the interpretation of H3 variants specific to diffuse midline glioma, H3 K27-altered and diffuse hemispheric glioma, H3 G34-mutant.</div><div>The main proposed specifications to the ClinGen/CGC/VICC Oncogenicity SOP include: (1) the incorporation of trimethylation loss at the K27 residue and functional studies at G34 into evidence code OS2 and (2) stipulation of location at a 'conserved residue affecting epigenetic modification (e.g. histone H3 K27, G34, or K36)' for evidence code OM1.</div><div>The main proposed modifications to the ClinGen/CGC/VICC Oncogenicity SOP include: (1) an 'OS1_moderate' criterion (2 points), allowing for the same amino acid change as a previously established oncogenic variant in a homologous H3 gene; (2) an 'OS2_supportive' criterion (1 point), incorporating supportive evidence of frequent co-occurring variants (e.g. TP53, PDGFRA, ACVR1) or other supportive evidence of histone H3 mutation (e.g. gene expression analysis); and (3) an alternate OP2 criterion (1 point) applied when clinicopathologic features align with a corresponding histone mutant glioma in the WHO Classification. This novel modification introduces clinicopathological correlation into the assessment of oncogenicity. Evidence specifications have also been made to the AMP/ASCO/CAP guidelines.</div><div>Evaluation of our proposed changes to the guidelines is underway in a defined set of pilot variants.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Pages S12-S13"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"41. Step 2 updates for the oncogenic assessment of FLT3 variants by the ClinGen FLT3 somatic cancer variant curation expert","authors":"Nathan Kopp ,&nbsp;Mani Coumarane ,&nbsp;Rong He ,&nbsp;Yuwen Li ,&nbsp;Somayyeh Fahiminiya ,&nbsp;Nikita Mehta ,&nbsp;Shivani Golem ,&nbsp;Xiaonan Zhao ,&nbsp;Yiming Zhong ,&nbsp;Haluk Kavus ,&nbsp;Xiangqiang Shao ,&nbsp;Rashmi Kanagal-Shamanna ,&nbsp;Jason Saliba ,&nbsp;Obi Griffith ,&nbsp;Malachi Griffith ,&nbsp;Xinjie Xu ,&nbsp;Kilannin Krysiak ,&nbsp;Arpad Danos","doi":"10.1016/j.cancergen.2024.08.043","DOIUrl":"10.1016/j.cancergen.2024.08.043","url":null,"abstract":"<div><div>Variant interpretation guidelines aid genetic professionals in assessing the strength of evidence for the variant pathogenicity and clinical significance. Currently, there are no standard guidelines for evaluation of <em>FLT3</em> variants, leading to variability in interpretation of <em>FLT3</em> tyrosine kinase and non-tyrosine kinase variants. The FLT3 Somatic Cancer Variant Curation Expert Panel (SC-VCEP), within the ClinGen Somatic Cancer CDWG, is actively developing the variant oncogenicity interpretation rules for the <em>FLT3</em> gene using ClinGen/CGC/VICC (PMID: <span><span>35101336</span><svg><path></path></svg></span>) to facilitate accurate classification of <em>FLT3</em> variants.</div><div>We will provide an update on the <em>FLT3</em>-specific modifications to evidence criteria OP1/SBP1 and OP4/SBS1. To address OP1/SBP1 we assessed multiple <em>in silico</em> prediction tools and their performance on FLT3-specific variants. Based on the analysis, we selected ClinPred and REVEL as optimal prediction tools for further evaluation during the pilot phase. We also modify the population allele frequency criteria for OP4/SBS1 using the spectrum of allele frequency of <em>FLT3</em> variants. Recognizing the need for applicability to internal tandem duplication (ITD) variants, the strength of OM2 has been increased to OM2_strong for this variant type. With these updates, all rules have been evaluated and modifications/specifications proposed for OVS1, OS2/SBS2, OS3/OM3/OP3, OM1, OM2, OP1/SBP1, OP2, SBVS1, and OP4/SBS1. Once approved, the validity of the rules will be assessed on a set of pilot variants.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S13"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}