Cancer Variant Interpretation Research Articles

39. Modifying cancer variant interpretation guidelines for the curation of histone H3 variants: The 'next step' of the Cl

39. Modifying cancer variant interpretation guidelines for the curation of histone H3 variants: The 'next step' of the Cl

16. ClinGen Cancer Variant Interpretation (CVI) Committee: Pilot guidance for somatic cancer variant curation expert panels

16. ClinGen Cancer Variant Interpretation (CVI) Committee: Pilot guidance for somatic cancer variant curation expert panels

Opportunistic genetic screening increases the diagnostic yield and is medically valuable for care of patients and their relatives with hereditary cancer

BackgroundMultigene panel testing by next-generation sequencing (MGP-NGS) enables the detection of germline pathogenic or likely pathogenic variants (PVs/LPVs) in genes beyond those associated with a certain cancer phenotype. Opportunistic genetic...

Abstract 6569: ClinGen Somatic and CIViC collaborate to comprehensively evaluate somatic variants in cancer

Abstract The comprehensive evaluation of somatic variants in cancer requires consensus interpretation of their potential clinical significance (diagnosis, prognosis, and treatment response) and oncogenicity. To aid precision medicine through public interpretations, a multifaceted collaborative effort is required to bring together a community, structured guidance, and a public platform. The over 200 multi-disciplinary experts in the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG) provide a community that develops data curation guidelines and standards and curates evidence to determine the clinical significance and oncogenicity of somatic alterations in cancer. The Somatic CDWG established the Pediatric Cancer, Hematological Cancer, and Solid Tumor Taskforces to facilitate membership growth and targeted curation projects. Within these Taskforces, Somatic Cancer Variant Curation Expert Panels (SC-VCEPs) are developed through a 4-step approval process adapted from ClinGen germline VCEP procedures. Five SC-VCEPs (NTRK-fusions, FGFR variants, FLT3 variants, Histone H3 variants, and BCR::ABL1-like B-ALL alterations) are working through the approval process and one (Established Significance) is in the planning stage. SC-VCEPs tailor AMP/ASCO/CAP [PMID:27993330] and ClinGen/CGC/VICC Oncogenicity [PMID:35101336] guidelines, or create new classification guidance to aid granular assessment of their genomic alterations of interest. The Clinical Interpretations of Variants in Cancer (CIViC) knowledgebase provides the public platform for the Taskforces and SC-VCEPs to display their high-quality somatic cancer variant interpretations. These groups curate evidence from published literature and create Assertions summarizing evidence collected. These Assertions are further disseminated through other resources like ClinVar and the Variant Interpretation for Cancer Consortium (VICC) MetaKB. CIViC supports the application of AMP/ASCO/CAP tiering and levels for clinical significance Assertions. CIViC recently created Oncogenic Assertions, which supports the application of ClinGen/CGC/VICC codes. Three SC-VCEPs (FGFR, FLT3, and Histone H3) are tailoring the ClinGen/CGC/VICC Oncogenicity guidelines to their specific genes and CIViC will enable their ClinGen-approved, modified codes to be applied directly to their Oncogenic Assertions. Also, two SC-VCEPs (NTRK and BCR::ABL1-like) are developing fusion specific oncogenicity classification guidelines, which will be applied to their fusion specific CIViC Oncogenic Assertions. ClinGen Somatic groups have generated 695 CIViC Evidence Items and 33 Assertions from over 400 published papers. These numbers will continue to grow along with the development of more SC-VCEPs. ClinGen Somatic and CIViC foster collaboration, innovation, and most importantly the advancement of precision medicine. Citation Format: Jason Saliba, Arpad Danos, Kilannin Krysiak, Adam Coffman, Susanna Kiwala, Joshua McMichael, Cameron J. Grisdale, Ian King, Shamini Selvarajah, Xinjie Xu, Rashmi Kanagal-Shamanna, Laveniya Satgunaseelan, David Meredith, Mark Evans, Charles G. Mullighan, Yassmine Akkari, Gordana Raca, Angshumoy Roy, Alex H. Wagner, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith, on behalf of the ClinGen Somatic Clinical Domain Working Group. ClinGen Somatic and CIViC collaborate to comprehensively evaluate somatic variants in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6569.

CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase.

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing>3200 variants in>470 genes from>3100 publications.

112. ClinGen Somatic Cancer Variant Interpretation (CVI) committee and the Somatic Cancer expert panel process

The Clinical Genome Resource (ClinGen) Somatic Working Group (WG) is actively developing a somatic cancer variant curation expert panel (SC-VCEP) process that parallels the process developed by ClinGen for monogenic disorders. A critical aspect of the latter is the Sequence Variant Interpretation (SVI) WG, which provides guidance on applying the ACMG/AMP classification framework and VCEP specification approval. The ClinGen Somatic Cancer Variant Interpretation Committee (CVI) is a parallel effort to provide input and oversight in developing specifications based on the AMP/ASCO/CAP somatic variant interpretation guidelines. The CVI has 30 members, with representation from academic institutions and commercial laboratories and broad expertise from oncologists, pathologists, clinicians, clinical/laboratory geneticists, researchers and informaticians. The Somatic WG has three SC-VCEPs in the 4-step expert panel process (see abstract from Saliba et al). The CVI has been actively providing feedback on rules specifications. Although the AMP/ASCO/CAP guidelines reduce interpretation discrepancy, subjective elements remain and require substantial clarification. The CVI, in collaboration with GA4GH VICC and the Cancer Genomics Consortium (CGC) participated in development of Standard Operating Procedures (SOP) for the classification of oncogenic variants (PMID:35101336). SC-VCEPs will utilize this SOP in curating SNVs or small deletions/insertions. Upcoming projects focus on evaluating somatic functional assays, standardizing somatic gene-disease curation and further developing the process to review and approve SC-VCEP specifications. Through the development of a SC-VCEP process, we aim to create greater consistency and accuracy of cancer variant interpretations for the improvement of patient care and genomic medicine.

84. Benefits of integrating an open-source knowledgebase in a precision oncology workflow

Next-generation sequencing is revolutionizing precision oncology, but vast amounts of sequence data must be processed and mined to reveal clinically relevant alterations that can inform patient care. The Personalized OncoGenomics (POG) program at BC Cancer utilizes whole genome and transcriptome analysis, providing a comprehensive view of advanced cancer patient tumours. This analysis relies on curated clinical knowledgebases linking cancer variants and their clinical relevance, but the breadth and utility of these can be limited by proprietary access or limited coverage. CIViC (Clinical Interpretation of Variants in Cancer) is an open-access, crowd-sourced knowledgebase of clinically relevant cancer variants that aims to address these limitations, and is one of several sources used for variant interpretation in POG. Based on a retrospective cohort of POG cases, we evaluated the knowledgebase coverage of genes and variants involved in treatment recommendations from the molecular tumour board (MTB). In a preliminary analysis, we found more than 95% of patients had an alteration considered clinically actionable by the MTB, demonstrating the benefit of combined genome and transcriptome analysis. We found that knowledge from CIViC represented nearly 50% of therapeutic evidence reported at the MTB, emphasizing the role of open-access knowledge in precision oncology. Additionally, by prospectively examining the levels and sources of evidence in patient reports, we identified areas where additional knowledgebase curation would most impact alignment with clinical utility, highlighting genome signatures as a critical area for future curation efforts. We also considered the impact of quality of evidence on MTB recommendations and patient treatments.

120. Expert curation of FLT3 variants by the ClinGen FLT3 Somatic Cancer Variant Curation expert panel

FMS-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase with key roles in the survival, proliferation, and differentiation of hematopoietic cells. FLT3 variants are the most common alterations in acute myeloid leukemia (AML), occurring in approximately 30% of all AML cases. Routine screening for FLT3 variants in AML patients is recommended by the World Health Organization and European LeukemiaNet guidelines, as early detection of FLT3 variants guides therapy using FDA-approved FLT3 inhibitors to achieve better outcomes. However, there is a lack of consistency in the curation, interpretation, and reporting of FLT3 sequence variants among molecular pathologists in the clinical diagnostic setting. To address these issues, the ClinGen Somatic Cancer Clinical Domain Working Group (CDWG) formed the FLT3 Somatic Cancer Variant Curation Expert Panel (SC-VCEP), which is composed of 24 multi-disciplinary experts including oncologists, hematopathologists, molecular pathologists, clinical lab directors, and biocurators with expertise in hematological malignancies. Our FLT3 SC-VCEP received step 1 approval from the ClinGen CDWG Oversight Committee in December 2021. This SC-VCEP is working to establish a consensus on interpreting FLT3 variants according to the AMP/ASCO/CAP and ClinGen/CGC/VICC guidelines (PMIDs: 27993330, 35101336). The FLT3 SC-VCEP will utilize the expertise of clinical laboratory practice standards for evaluating variants and will curate these interpretations in the Clinical Interpretations of Variants in Cancer (CIViC) platform with an aim to apply the newly created and approved rules to generate expert-panel approved FLT3 variant submissions. Upon consensus classification, these interpretations will also be publicly available through ClinVar.

68. Integrative analysis of genomic and transcriptomic data using RegTools to identify splice-altering mutations within bulk

The interpretation of variants in cancer is often focused on genomic alterations that have a known coding consequence. This analysis strategy excludes somatic mutations in non-coding regions of the genome and even exonic mutations that may have unidentified regulatory consequences. To address this issue, we created RegTools, a software suite that integrates analysis of variant calls from genomic data with evidence of expressed splice junctions from transcriptomic data to efficiently identify variants that may cause aberrant splicing in tumors. To date, we have applied RegTools to over 9,000 bulk RNA-Seq samples from TCGA and clinical cohorts from Washington University to identify somatic variants that are associated with alternative splicing patterns within these tumors. We discovered 235,778 splice-altering events across 158,200 unique variants and 131,212 unique junctions.Only 1.4 percent of these mutations were previously discovered by similar attempts, while 98.6 percent are novel findings. We also applied RegTools to single cell RNA-Seq (scRNA) data from MC6BC, a transplantable organoid model of urothelial carcinoma with features of human basal-squamous urothelial carcinoma, and identified tumor-specific somatic variants leading to novel splice junctions at single-cell resolution. To our knowledge, this is the first analysis that identifies splice-altering variants within scRNA data. Future work will include utilizing RegTools to predict the novel proteins resulting from splice-altering variants and their neoantigenicity. RegTools is freely available and open-source (www.regtools.org) and all analysis scripts are provided within the project's GitHub repo (https://github.com/griffithlab/regtools).

Druggable gene alterations in Japanese patients with rare malignancy

Without a current standard of care, patients with rare malignancy are subjected to precision oncology with next-generation sequencing to identify a course of treatment. We sought to establish the clinical relevance of comprehensive genomic profiling (CGP) among patients with rare malignancy. Rare malignancy was defined using the Rare Cancers in Europe definition (<6 cases per 100,000 individuals). We analyzed gene mutations, fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Level A gene alterations, categorized using Clinical Interpretations of Variants in Cancer and MD Anderson Knowledge Base for Precision Oncology, were considered druggable. Rare malignancy accounted for 149 (45%) cases, with female genital cancers (32%) most common. Among the rare malignancy cases, we identified a lower frequency of mutation in TP53 (41% vs. 60%, P<0.001), KRAS (13% vs. 43%, P<0.001) and APC (3% vs. 25%, P<0.001), and a higher frequency of ARID1A mutation (14% vs. 6%, P=0.03), as compared with common malignancies. TMB-high and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 37 patients with rare malignancy; this percentage tended to be higher than that for patients with common malignancies (25% vs. 17%, P=0.08). Common druggable alterations were BRAF V600E, ERBB2 amplification, PIK3CA E542K, and BRCA1/2 variant. Five of the 37 patients with druggable alterations received genome-driven treatment. There was no significant difference in overall survival between the rare and common malignancy groups. Our results provide clues for future clinical development and treatment success among Japanese patients with rare cancers.

Identifying Lethal Dependencies with HUGE Predictive Power.

Simple SummaryThis work shows that the predictions of lethal dependencies (LEDs) between genes can be dramatically improved by incorporating the “HUb effect in Genetic Essentiality” (HUGE) of gene alterations. In three genome-wide loss-of-function screens—Project Score, CERES score and DEMETER score—LEDs are identified with 75 times larger statistical power than using state-of-the-art methods. In AML, we identified LEDs not recalled by previous pipelines, including FLT3-mutant genotypes sensitive to FLT3 inhibitors. Interestingly, in-vitro validations confirm lethal de-pendencies of either NRAS or PTPN11 depending on the NRAS mutational status.Recent functional genomic screens—such as CRISPR-Cas9 or RNAi screening—have fostered a new wave of targeted treatments based on the concept of synthetic lethality. These approaches identified LEthal Dependencies (LEDs) by estimating the effect of genetic events on cell viability. The multiple-hypothesis problem is related to a large number of gene knockouts limiting the statistical power of these studies. Here, we show that predictions of LEDs from functional screens can be dramatically improved by incorporating the “HUb effect in Genetic Essentiality” (HUGE) of gene alterations. We analyze three recent genome-wide loss-of-function screens—Project Score, CERES score and DEMETER score—identifying LEDs with 75 times larger statistical power than using state-of-the-art methods. Using acute myeloid leukemia, breast cancer, lung adenocarcinoma and colon adenocarcinoma as disease models, we validate that our predictions are enriched in a recent harmonized knowledge base of clinical interpretations of somatic genomic variants in cancer (AUROC > 0.87). Our approach is effective even in tumors with large genetic heterogeneity such as acute myeloid leukemia, where we identified LEDs not recalled by previous pipelines, including FLT3-mutant genotypes sensitive to FLT3 inhibitors. Interestingly, in-vitro validations confirm lethal dependencies of either NRAS or PTPN11 depending on the NRAS mutational status. HUGE will hopefully help discover novel genetic dependencies amenable for precision-targeted therapies in cancer. All the graphs showing lethal dependencies for the 19 tumor types analyzed can be visualized in an interactive tool.

Abstract 1156: Genome Nexus: A comprehensive resource for the annotation and interpretation of genomic variants in cancer

Abstract Interpreting genomic variants in tumor samples presents a challenge in research and the clinical setting. A major barrier is that information about variants is fragmented across disparate databases, and aggregating information from these requires building extensive infrastructure. To this end, we have developed Genome Nexus, a one stop shop for variant annotation, equipped with a powerful API for bulk annotation of variants and a user friendly interface for cancer researchers. Genome Nexus is available at https://www.genomenexus.org. It a) aggregates variant information from a large number of sources that are relevant to cancer research and clinical applications; b) allows high-performance programmatic access to the aggregated data via a unified API; c) provides a search interface and a reference page for individual cancer variants; d) provides user-friendly tools for annotating variants in patients; e) is freely available under an open source license and can be installed in a private cloud or local environment. Genome Nexus contains annotations from more than a dozen resources, including those that provide variant effect information (VEP), protein sequence annotation (Uniprot, Pfam, dbPTM), functional consequence prediction (Polyphen-2, Mutation Assessor, SIFT), population prevalence (gnomAD, dbSNP, ExAC), cancer population prevalence (Cancer Hotspots, SignalDB) and clinical actionability (OncoKB, CIViC, Clinvar). The annotations can be accessed through the website, the API, and a command line client. Genome Nexus is unique in providing a user friendly interface specific to cancer that allows high performance annotation of any variant. It is the main annotation service for the popular cancer genomics tool cBioPortal, which serves thousands of users daily. It is also offered as a standalone tool for annotation, allowing researchers and clinicians as well as genomic infrastructure developers to leverage it directly in their own workflows. For example, a local installation of Genome Nexus is used for annotating all variants in AACR Project GENIE. Citation Format: Ino de Bruijn, Xiang Li, Onur Sumer, Benjamin Gross, Robert Sheridan, Angelica Ochoa, Manda Wilson, Avery Wang, Hongxin Zhang, Aaron Lisman, Adam Abeshouse, Sander Rodenburg, Sjoerd van Hagen, Remond Fijneman, Gerrit Meijer, Nikolaus Schultz, Jianjiong Gao. Genome Nexus: A comprehensive resource for the annotation and interpretation of genomic variants in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1156.

Abstract 1194: Redesigning CIViC: Enhancing the structured curation of complex cancer variant data

Abstract The Clinical Interpretation of Variants in Cancer (CIViC; www.civicdb.org) knowledgebase is a curation platform designed to capture evidence from the published literature which support or refute the significance of genomic variants in various cancer types. Since the launch of the beta user interface in 2014, this knowledgebase has undergone substantial evolution and redesign to support the needs of the clinical and research communities. Significant work has been done by the community to release guidelines and resources to support cancer variant interpretation. CIViC is a crowd sourced, expert moderated resource with a community of over 300 active curators. In response to community feedback, evolving guidelines and improved understanding of the genetics of cancer, we have developed CIViC 2.0, a major redesign that expands the capabilities of this widely used resource. CIViC 2.0 has been designed to support complex variant relationships (termed molecular profiles in CIViC) such as the poor prognostic impact of the combination of variants in FLT3, DNMT3A and NPM1 in acute myeloid leukemia. These highly structured molecular profiles link details about each constituent variant, including genomic coordinates, HGVS, aliases, and additional metadata. Molecular profiles will also support the absence of a variant, which has become critical in targeted therapy decision making such as colorectal cancer where EGFR expression without a KRAS variant is an indication for targeted inhibitor therapy. These molecular profiles also support structural variants. While fusions have always been supported, CIViC 2.0 will support complex genomic coordinate or cytoband specific queries. Significant technical changes have improved the speed and performance of the UI and the underlying API. A complete redesign of the API, utilizing GraphQL, empowers users to ask more complex questions and more deeply explore this highly curated data. More robust data schemas and comprehensive validation of evidence structure will allow for the programmatic submission of new evidence. By utilizing site-wide full text faceted search, identifying relevant content in summaries, evidence items, or even curator comments is straightforward. The CIViC 2.0 redesign supports the ever-increasing complexity of cancer variant information and provides a powerful tool to explore and utilize the carefully curated data within the knowledgebase for a multitude of questions related to basic, translational, and clinical research. Citation Format: Kilannin C. Krysiak, Adam C. Coffman, Susanna Kiwala, Joshua F. McMichael, Arpad M. Danos, Jason Saliba, Cameron J. Grisdale, Jake Lever, Lana Sheta, Shruti Rao, Alex H. Wagner, Malachi Griffith, Obi L. Griffith. Redesigning CIViC: Enhancing the structured curation of complex cancer variant data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1194.

Abstract 5735: Druggable gene alterations in Japanese patients with rare malignancy

Abstract Background: In the absence of a current standard of care, precision oncology with next-generation sequencing provides an important therapeutic option for patients with rare malignancy. Here, we sought to establish the clinical relevancy of comprehensive genomic profiling (CGP) for patients with rare malignancy. Methods: We reviewed 341 patients who underwent CGP (FoundationOne CDx; OncoGuide NCC OncoPanel System)in our institution between 2019 and 2021. Cases were classified as common or rare malignancy based on the Rare Cancers in Europe (RARECARE) definition (incidence of &amp;lt;6 cases per 100,000 individuals). We analyzed the genomic features in the rare malignancy cohort, including gene mutations, gene fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Gene variants, amplifications, and fusions categorized as evidence level A using Clinical Interpretations of Variants in Cancer (CIViC) and MD Anderson Knowledge Base for Precision Oncology were considered as druggable alterations. CGP testing was used to calculate overall survival (OS) to death or at the last follow-up. Results: With the exception of 7 unclassifiable cases, rare malignancy accounted for 149 of the 334 cases (45%), with the most common being female genital cancers (32%), followed by digestive cancers (24%), sarcoma (16%), and others (28%). Many (83%) of the patients with rare malignancy harbored at least one pathogenic/likely-pathogenic variant. The commonly mutated genes were TP53 (41%), PIK3CA (20%), ARID1A (14%), and KRAS (13%). ERBB2amplification was detected in 6% of patients (median copy number, 8). Gene fusion in EWSR1 was found in 4% of patients (sarcoma) and in FGFR2 in 1% (cholangiocarcinoma and salivary duct carcinoma). TMB-high (≥10 mut/Mb) and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 36 patients; this percentage was not significantly different to that of common malignancy (24% vs. 17%, P=0.10). The common druggable alterations were BRAF V600E (n=10), ERBB2 amplification (n=9), PIK3CA E542K (n=6), and BRCA1/2 variant (n=6). There was no significant difference in OS between the rare and common malignancy groups (1-year OS rate: 62% vs. 46%, P=0.24). Conclusion: In this study, the ratio of rare malignancy was higher than that typically found in previous epidemiological studies (about 20%-25%). We observed no adverse impact for OS, which might be due to the high number of patients (n=48) with intractable pancreatic cancer. Remarkably, &amp;gt;20% of patients harbored a potential druggable alteration. Our results suggest the clinical relevance of CGP for patients with rare malignancy, and its potential utility to provide clues for future clinical development. Citation Format: Akihiro Ohmoto, Naomi Hayashi, Ippei Fukada, Masumi Yamazaki, Mayu Yunokawa, Akiyoshi Kasuga, Eiji Shinozaki, Arisa Ueki, Akiko Tonooka, Kengo Takeuchi, Seiichi Mori, Kazuma Kiyotani, Shunji Takahashi. Druggable gene alterations in Japanese patients with rare malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5735.

Abstract 1192: The Clinical Genome Resource (ClinGen) somatic cancer clinical domain working group

Abstract Interpretation of the clinical significance of somatic gene variants in cancer remains a major challenge in cancer diagnosis, prognosis and treatment response prediction. We will report on progress and plans of the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG). The CDWG membership consists of over 150 multi-disciplinary experts in cancer biology, oncology, pathology, genetics, genomics and informatics. The mission of the ClinGen Somatic Cancer CDWG is to facilitate the development of data curation guidelines and standards to determine the clinical significance of somatic alterations in cancer, thereby enhancing the usability, dissemination and implementation of cancer somatic changes in the ClinGen resource and other knowledgebases including CIViC, ClinVar, and the Variant Interpretation for Cancer Consortium (VICC) MetaKB. Our goal is to create high-quality assertions of the clinical significance of specific somatic variants in cancer by leveraging the CIViC curation interface, adapting the germline procedures of ClinGen to somatic variant interpretation, and implementing the interoperability standards of the Global Alliance for Genomics and Health (GA4GH). The ClinGen Somatic effort is overseen by the Somatic CDWG and reports progress to the overall ClinGen consortium. There are Somatic Cancer subdomains focused on particular clinically important domains of cancer variant interpretation including three Task Forces (covering Pediatric Cancer, Hematologic Cancer, and Solid Tumors) and a growing number of Somatic Cancer Variant Curation Expert Panels (SC-VCEPs). To improve quality and consistency of clinical interpretations, each candidate somatic cancer VCEP must complete a four step approval process adapted from ClinGen’s work in Germline disease domains. The Somatic CDWG works to ensure that each group is aware of available training materials and detailed standard operating procedures. Each SC-VCEP also coordinates with the ClinGen Cancer Variant Interpretation Committee (CVI) whose goal is to support development of granular specifications for the AMP/ASCO/CAP guidelines for somatic variant interpretation. New SC-VCEPs are anticipated to focus on specific clinically relevant genes, pathways, disease entities, variant classes or treatment modalities. Currently, three SC-VCEPs have begun to work through the four step process (focused on FGFR mutations, NTRK fusions, and FLT3 mutations respectively), and two more SC-VCEPs are in the planning stage (Histone H3 and Ph-like ALL). To date, ClinGen Somatic groups have contributed 619 evidence lines into CIViC from 353 published papers and 21 assertions of clinical significance. Input from the AACR community is critical for the establishment of new SC-VCEPs that address areas of variant interpretation with the greatest need. Citation Format: Jason Saliba, Gordana Raca, Angshumoy Roy, Ian King, Shamini Selvarajah, Xinjie Xu, Rashmi Kanagal-Shamanna, Laveniya Satgunaseelan, David Meredith, Mark Evans, Alanna Church, Panieh Terraf, Yassmine Akkari, Heather E. Williams, Wan-Hsin Lin, Chimene Kesserwan, Deborah I. Ritter, Kilannin Krysiak, Arpad Danos, Alex Wagner, Marilyn M. Li, Dmitriy Sonkin, Jonathan S. Berg, Sharon E. Plon, Heidi L. Rehm, Shashikant Kulkarni, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith, on behalf of the ClinGen Somatic CDWG. The Clinical Genome Resource (ClinGen) somatic cancer clinical domain working group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1192.

Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK)

Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely. Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification. We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score. In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings.

Large scale genotype- and phenotype-driven machine learning in Von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype-phenotype data. Patient data weretranslated into standardized descriptions using Human Genome Variation Societygene variant nomenclature and Human Phenotype Ontologyterms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype-phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.

Genome Nexus: A Comprehensive Resource for the Annotation and Interpretation of Genomic Variants in Cancer.

Interpretation of genomic variants in tumor samples still presents a challenge in research and the clinical setting. A major issue is that information for variant interpretation is fragmented across disparate databases, and aggregation of information from these requires building extensive infrastructure. To this end, we have developed Genome Nexus, a one-stop shop for variant annotation with a user-friendly interface for cancer researchers and clinicians. Genome Nexus (1) aggregates variant information from sources that are relevant to cancer research and clinical applications, (2) allows high-performance programmatic access to the aggregated data via a unified application programming interface, (3) provides a reference page for individual cancer variants, (4) provides user-friendly tools for annotating variants in patients, and (5) is freely available under an open source license and can be installed in a private cloud or local environment and integrated with local institutional resources. Genome Nexus is available at https://www.genomenexus.org. It displays annotations from more than a dozen resources including those that provide variant effect information (variant effect predictor), protein sequence annotation (Uniprot, Pfam, and dbPTM), functional consequence prediction (Polyphen-2, Mutation Assessor, and SIFT), population prevalences (gnomAD, dbSNP, and ExAC), cancer population prevalences (Cancer hotspots and SignalDB), and clinical actionability (OncoKB, CIViC, and ClinVar). We describe several use cases that demonstrate the utility of Genome Nexus to clinicians, researchers, and bioinformaticians. We cover single-variant annotation, cohort analysis, and programmatic use of the application programming interface. Genome Nexus is unique in providing a user-friendly interface specific to cancer that allows high-performance annotation of any variant including unknown ones. Interpretation of cancer genomic variants is improved tremendously by having an integrated resource for annotations. Genome Nexus is freely available under an open source license.

DrugCVar: a platform for evidence-based drug annotation for genetic variants in cancer

Targeted therapy for cancer-related genetic variants is critical for precision medicine. Although several databases including The Clinical Interpretation of Variants in Cancer (CIViC), The Oncology Knowledge Base (OncoKB), The Cancer Genome Interpreter (CGI) and My Cancer Genome (MCG) provide clinical interpretations of variants in cancer, the clinical evidence was limited and miscellaneous. In this study, we developed the DrugCVar database, which integrated our manually curated cancer variant-drug targeting evidence from literature and the interpretations from the public resources. In total, 7830 clinical evidences for cancer variant-drug targeting were integrated and classified into 10 evidence tiers. Searching and browsing functions were provided for quick queries of cancer variant-drug targeting evidence. Also, batch annotation module was developed for user-provided massive genetic variants in various formats. Details, such as the mutation function, location of the variants in gene and protein structures and mutation statistics of queried genes in various tumor types, were also provided for further investigations. Thus, DrugCVar could serve as a comprehensive annotation tool to interpret potential drugs for cancer variants especially the massive ones from clinical cancer genomics studies. The database is available at http://drugcvar.omicsbio.info. Supplementary data are available at Bioinformatics online.

EP055: The Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group

Interpretation of the clinical significance of somatic variants in cancer remains a major challenge in cancer diagnosis, prognosis and treatment response prediction. Here, we report on progress and plans of the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG). The CDWG membership consists of over 150 multi-disciplinary experts in cancer biology, oncology, pathology, genetics, genomics, and informatics. The mission of the ClinGen Somatic Cancer CDWG is to facilitate the development of data curation guidelines and standards to determine the clinical significance of somatic alterations in cancer, thereby enhancing the usability, dissemination and implementation of cancer somatic variant interpretations in the ClinGen resource and other knowledgebases including the Clinical Interpretations of Variants in Cancer (CIViC), ClinVar, and the Variant Interpretation for Cancer Consortium (VICC) MetaKB.