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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.

Pediatric acute myeloid leukemia (AML) is genetically heterogenous (Olsson et al., 2016). t(X;6)(p11;q23) is a rare but recurrent chromosomal translocation in infant AML thought to be associated with male sex and basophilic differentiation (Dastugue et al., 1997). Here we report molecular characterization of AML with t(X;6)(p11;q23);MYB-GATA1 in two female infants and demonstrate preserved GATA1 expression in the sample tested. These findings further debunk a concept that this fusion was restricted to males, in whom it disrupts the only copy of the X-linked GATA1 gene, causing presumable complete loss of GATA1 function. Our data also demonstrate the power and efficiency of RNA sequencing for subclassification of leukemia on a clinically relevant timeline.

Background The hallmark of lipoblastoma is a PLAG1 fusion. PLAG1 protein overexpression has been reported in sporadic PLAG1-rearranged lipoblastomas. Methods We evaluated the utility of PLAG1 immunohistochemical staining (IHC) in 34 pediatric lipomatous tumors, correlating the results with histology and conventional cytogenetics, FISH and/or next generation sequencing (NGS) results. Results The study included 24 lipoblastomas, divided into 2 groups designated as “Lipoblastoma 1” with both lipoblastoma histology and PLAG1 rearrangement (n = 16) and “Lipoblastoma 2” with lipoblastoma histology but without PLAG1 cytogenetic rearrangement (n = 8), and 10 lipomas with neither lipoblastoma histology nor a PLAG1 rearrangement. Using the presence of a fusion as the “gold standard” for diagnosing lipoblastoma (Lipoblastoma 1), the sensitivity of PLAG1 IHC was 94%. Using histologic features alone (Lipoblastoma 1 + 2), the sensitivity was 96%. Specificity, as defined by the ability to distinguish lipoma from lipoblastoma, was 100%, as there were no false positives in the lipoma group. Conclusions Cytogenetics/molecular testing is expensive and may not be ideal for detecting PLAG1 fusions because PLAG1 fusions are often cytogenetically cryptic and NGS panels may not include all partner genes. PLAG1 IHC is an inexpensive surrogate marker of PLAG1 fusions and may be useful in distinguishing lipoblastomas from lipomas.

The small cell undifferentiated component of hepatoblastoma is an uncommon histologic component and is distinguished from small cell undifferentiated like pattern (originally called hepatoblastoma and now recognized to be malignant rhabdoid tumor) by the bi-allelic SMARCB1 mutations or copy number alterations in the latter. AT-rich interactive domain-containing protein 1A ( ARID1A) is a part of the ATP-dependent switch/sucrose non-fermentable complex assembly, but mutations have not been reported as drivers of malignant rhabdoid tumor. ARID1A mutations in hepatocellular carcinoma are associated with poor prognosis but its significance in hepatoblastoma is unknown. We report a unique case of hepatoblastoma in a 19-month-old female with an unusual/atypical small cell undifferentiated component with ARID1A and beta-catenin mutations. It had an aggressive clinical course despite treatment, with metastases to the left psoas muscle, perihepatic and paratracheal lymph nodes, spinal cord, and leptomeninges. Leptomeningeal metastases resulted in diffuse cerebral edema and death. The initial diagnostic biopsy did not reveal rhabdoid cells while all metastatic foci showed cells with rhabdoid morphology in the autopsy specimens. Although this rhabdoid component resembled malignant rhabdoid tumor morphologically, molecular analyses failed to show mutations or deletions of SMARCB1.

Detection of somatic genetic drivers is important for risk stratification and treatment selection in pediatric leukemias; however, newly recognized genetic markers may not be detected by routine karyotyping and fluorescence in situ hybridization (FISH). To identify the combination of assays that provides the highest detection rate for clinically significant molecular abnormalities, we tested 160 B- lymphoblastic leukemia (B-ALL) by karyotyping, FISH, chromosomal microarray analysis (CMA) and the custom next-generation sequencing (NGS) panel, OncoKidsⓇ. In addition, we tested 40 myeloid malignancies with karyotyping, chromosomal microarray analysis (CMA), and OncoKidsⓇ; 36/40 myeloid malignancies were also tested with FISH. In B-ALL, individual testing methods had the following diagnostic yields for the key genetic drivers: karyotype 34%; basic FISH panel 45%; FISH panel with IGH and CRLF2 probes 65%; CMA 48%; OncoKidsⓇ 39%. CMA and OncoKidsⓇ testing allowed detection of key genetic drivers in 42% of the samples that remained unknown upon testing by conventional methods. In myeloid malignancies, OncoKidsⓇ had the highest yield for detection of both primary and secondary DNA mutations and RNA fusions. Our data highlights the complementarity between CMA and NGS and conventional cytogenetics/FISH in pediatric leukemia diagnostics. Due to rapid turn-around-time, FISH may be useful as an initial screening method in B-ALL. Our data also suggests NGS testing with a comprehensive panel, despite a longer turnaround time, is a good alternative to karyotyping and FISH in pediatric AML due to its superior detection rate.

Gene fusions involving the neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2, and NTRK3, are well established oncogenic drivers in a broad range of pediatric and adult tumors. These fusions are also important actionable markers, predicting often dramatic response to FDA approved kinase inhibitors. Accurate interpretation of the clinical significance of NTRK fusions is a high priority for diagnostic laboratories, but remains challenging and time consuming given the rapid pace of new data accumulation, the diversity of fusion partners and tumor types, and heterogeneous and incomplete information in variant databases and knowledgebases. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to systematically address these challenges and create an expert-curated resource to support clinicians, researchers, patients and their families in making accurate interpretations and informed treatment decisions for NTRK fusion-driven tumors. We describe a system for NTRK fusion interpretation (including compilation of key elements and annotations) developed by the NTRK fusions SC-VCEP. We illustrate this stepwise process on examples of LMNA::NTRK1 and KANK1::NTRK2 fusions. Finally, we provide detailed analysis of current representation of NTRK fusions in public fusion databases and the CIViC knowledgebase, performed by the NTRK fusions SC-VCEP to determine existing gaps and prioritize future curation activities.

As guidelines, therapies, and literature on cancer variants expand, the lack of consensus variant interpretations impedes clinical applications. CIViC is a public domain, crowd-sourced, and adaptable knowledgebase of evidence for the Clinical Interpretation of Variants in Cancer, designed to reduce barriers to knowledge sharing and alleviate the variant interpretation bottleneck.

PURPOSE: Several professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. While these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (e.g., population frequency, functional and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation and importantly impacts patient care. Therefore, it’s essential to address this unmet need. METHODS: Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium (CGC), and the Variant Interpretation for Cancer Consortium (VICC) used a consensus approach to develop a Standard Operating Procedure (SOP) for the classification of oncogenicity of somatic variants. RESULTS: This comprehensive SOP has been developed to improve consistency in somatic variant classification, and has been validated on 94 somatic variants in ten common cancer-related genes. CONCLUSION: The comprehensive SOP is now available for classification of oncogenicity of a somatic variant.

The hallmark of lipoblastoma is a PLAG1 fusion. PLAG1 protein overexpression has been reported in sporadic PLAG1-rearranged lipoblastomas.We evaluated the utility of PLAG1 immunohistochemical staining (IHC) in 34 pediatric lipomatous tumors, correlating the results with histology and conventional cytogenetics, FISH and/or next generation sequencing (NGS) results.The study included 24 lipoblastomas, divided into 2 groups designated as "Lipoblastoma 1" with both lipoblastoma histology and PLAG1 rearrangement (n = 16) and "Lipoblastoma 2" with lipoblastoma histology but without PLAG1 cytogenetic rearrangement (n = 8), and 10 lipomas with neither lipoblastoma histology nor a PLAG1 rearrangement. Using the presence of a fusion as the "gold standard" for diagnosing lipoblastoma (Lipoblastoma 1), the sensitivity of PLAG1 IHC was 94%. Using histologic features alone (Lipoblastoma 1 + 2), the sensitivity was 96%. Specificity, as defined by the ability to distinguish lipoma from lipoblastoma, was 100%, as there were no false positives in the lipoma group.Cytogenetics/molecular testing is expensive and may not be ideal for detecting PLAG1 fusions because PLAG1 fusions are often cytogenetically cryptic and NGS panels may not include all partner genes. PLAG1 IHC is an inexpensive surrogate marker of PLAG1 fusions and may be useful in distinguishing lipoblastomas from lipomas.

Malignant rhabdoid tumor (MRT) is a rare, SWItch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 ( SMARCB1)-deficient, aggressive tumor, occurring predominantly in children below 3 years of age. Primary adrenal MRT is extremely rare, with only 3 cases reported in the literature. A previously healthy 14-year-old female presented with left upper quadrant/epigastric abdominal pain. Imaging studies revealed an 8.0 × 8.0 × 6.5 cm, heterogeneous, partially enhancing mass along the superior margin of the left kidney encasing the adrenal gland. Surgical resection of the tumor revealed a hypercellular heterogeneous neoplasm arising from the adrenal gland. It was composed predominantly of primitive small round blue cells with focal true rosettes and areas of vague glandular epithelial differentiation and chondroid differentiation. Classic rhabdoid-type cytoplasmic inclusions were focally present. Mitoses, tumor necrosis, and hemorrhage were readily seen. Tumor cells showed complete loss of SMARCB1 (INI1) nuclear staining, demonstrated strong, and diffuse positivity for glypican 3, patchy positivity for CD99, cytokeratin, Sal-like protein 4, Lin-28 homolog A, epithelial membrane antigen, and S100. Molecular studies revealed biallelic frameshift mutations in the SMARCB1 gene (c.673delG and c.683dupT) without pathogenic copy number aberrations. The histologic, immunohistochemical, and molecular findings support a diagnosis of MRT. The unusual age, location, and mutations of this case expand the clinicopathologic and molecular spectrum of MRT.

Copy-number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array and next-generation sequencing–based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health. To assist clinical laboratories in the classification and reporting of CNVs, irrespective of the technology used to identify them, the American College of Medical Genetics and Genomics has developed the following professional standards in collaboration with the National Institutes of Health (NIH)–funded Clinical Genome Resource (ClinGen) project. This update introduces a quantitative, evidence-based scoring framework; encourages the implementation of the five-tier classification system widely used in sequence variant classification; and recommends “uncoupling” the evidence-based classification of a variant from its potential implications for a particular individual. These professional standards will guide the evaluation of constitutional CNVs and encourage consistency and transparency across clinical laboratories.

Childhood cancers present unique challenges for variant interpretation in a clinical context due to their rarity, low mutation burden, diversity of molecular alterations, and heterogeneity among patients. Consequently, genes and variants associated with childhood tumors are under-represented in public cancer databases and knowledgebases. A focused effort is needed for the structured curation of genetic variant-level data to document diagnostic, prognostic, and therapeutic biomarkers for childhood cancers. The Pediatric Cancer Curation Advancement Subcommittee (PCCAS), a collaboration between the Clinical Interpretations of Variants in Cancer knowledgebase (CIViC; civicdb.org), the ClinGen Somatic Pediatric Cancer Taskforce, Disease Ontology (DO; disease-ontology.org) and CIViCmine (bionlp.bcgsc.ca/civicmine/), is addressing this challenge through enhanced curation, tagging, and automation. PCCAS created a pediatric specific curation standard operating procedure (SOP) to harmonize pediatric evidence entered in CIViC. Our SOP provides general guidance and considerations to define and classify childhood cancers and to represent childhood cancer evidence on a spectrum of age-related incidence and presentation. For instance, pediatric evidence in CIViC is now tagged using Human Phenotype Ontology (HPO) age of onset terms, allowing pediatric evidence to be easily searched, tracked, and sorted. We also initiated the addition of new age of onset terms to enhance the granularity of these tags. WHO ICD-O nomenclature has been chosen for pediatric disease classification in CIViC. ICD-O provides updated terminology including specific genetic subtypes, which are important in pediatric cancers where their underlying molecular profiles often define the disease. To aid curator selection of disease, we verified pediatric relevant ICD-O terms inclusion in DO and restructured DO disease hierarchies to ensure proper mapping. CIViC highlights our pediatric cancer initiative in multiple areas including a homepage feature linking directly to a dedicated pediatric advanced search that returns all evidence tagged with pediatric or young adult age of onset. Most importantly, our childhood specific SOP and initiatives are included in all ClinGen Somatic Cancer and CIViC training sessions for consistent implementation. CIViCmine supports CIViC by using natural language processing to identify important cancer biomarkers in the literature. To better identify pediatric biomarkers, we are adapting and refining CIViCmine to use MeSH terms and other approaches to enhance accuracy in the identification of childhood evidence in both the literature and CIViC. In conclusion, implementation of these procedures, features, and automation are pushing to make childhood cancer variant evidence more accessible and interpretable. Citation Format: Jason Saliba, Jake Lever, Kilannin Krysiak, Arpad Danos, Alex Wagner, Heather E. Williams, Laveniya Satgunaseelan, David Meredith, Cameron J. Grisdale, Chimene Kesserwan, Jianling Ji, Shruti Rao, Catherine Cottrell, Alanna Church, Mark Evans, Yasmina Jaufeerally-Fakim, Lynn M. Schriml, Angshumoy Roy, Gordana Raca, Malachi Griffith, Obi L. Griffith. Enhancing pediatric cancer variant curation and representation through standardized classification and automation [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 1193.

Multiple studies have demonstrated the utility of chromosomal microarray (CMA) testing to identify clinically significant copy number alterations (CNAs) and copy-neutral loss-of-heterozygosity (CN-LOH) in myeloid malignancies. However, guidelines for integrating CMA as a standard practice for diagnostic evaluation, assessment of prognosis and predicting treatment response are still lacking. CMA has not been recommended for clinical work-up of myeloid malignancies by the WHO 2016 or the NCCN 2017 guidelines but is a suggested test by the European LeukaemiaNet 2013 for the diagnosis of primary myelodysplastic syndrome (MDS). The Cancer Genomics Consortium (CGC) Working Group for Myeloid Neoplasms systematically reviewed peer-reviewed literature to determine the power of CMA in (1) improving diagnostic yield, (2) refining risk stratification, and (3) providing additional genomic information to guide therapy. In this manuscript, we summarize the evidence base for the clinical utility of array testing in the workup of MDS, myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and myeloproliferative neoplasms (MPN). This review provides a list of recurrent CNAs and CN-LOH noted in this disease spectrum and describes the clinical significance of the aberrations and how they complement gene mutation findings by sequencing. Furthermore, for new or suspected diagnosis of MDS or MPN, we present suggestions for integrating genomic testing methods (CMA and mutation testing by next generation sequencing) into the current standard-of-care clinical laboratory testing (karyotype, FISH, morphology, and flow).

Synovial sarcoma (SS) arising within a knee joint is extremely rare, with 10 reported cases in pediatric and adolescent patients in English literature. Its rarity and nonspecific clinical and radiological features pose a diagnostic challenge. We present two cases of primary intra-articular SS of left knee to enhance awareness of this entity. One patient is a 17-year-old male complained of left knee pain and gait abnormality for 9 years. The other one is a 13-year-old female presented with left knee pain for one year. Both cases were clinically diagnosed as benign joint lesion and underwent biopsies. Histological examination, immunohistochemical staining and molecular study confirmed that both patients had primary intra-articular SS, monophasic spindle cell type. Intraarticular SS should be considered as a potential diagnosis with unexplained long-standing knee pain.

Context.— One goal of the joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee is to ensure the accurate detection and description of chromosomal abnormalities in both constitutional and neoplastic specimens, including hematologic neoplasms. Objective.— To report a 20-year performance summary (1999–2018) of conventional chromosome challenges focusing on hematologic neoplasms. Design.— A retrospective review was performed from 1999 through 2018 to identify karyotype challenges specifically addressing hematologic neoplasms. The overall performance of participants was examined to identify potential recurring errors of clinical significance. Results.— Of 288 total conventional chromosome challenges from 1999–2018, 87 (30.2%) were presented in the context of a hematologic neoplasm, based on the provided clinical history, specimen type, and/or chromosomal abnormalities. For these 87 hematologic neoplasm challenges, 91 individual cases were provided and graded on the basis of abnormality recognition and karyotype nomenclature (ISCN, International System for Human Cytogenomic [previously Cytogenetic] Nomenclature). Of the 91 cases, 89 (97.8%) and 87 (95.6%) exceeded the required 80% consensus for grading of abnormality recognition and correct karyotype nomenclature, respectively. The 2 cases (2 of 91; 2.2%) that failed to meet the 80% consensus for abnormality recognition had complex karyotypes. The 4 cases (4 of 91; 4.4%) that failed to meet the 80% consensus for correct karyotype nomenclature were the result of incorrect abnormality recognition (2 cases), missing brackets in the karyotype (1 case), and incorrect breakpoint designation (1 case). Conclusions.— This 20-year review demonstrates clinical cytogenetics laboratories have been and continue to be highly proficient in the detection and description of chromosomal abnormalities associated with hematologic neoplasms.

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface (search.cancervariants.org) for exploring the harmonized interpretations from these six knowledgebases., This analysis presents a harmonized meta-knowledgebase to facilitate clinical interpretation of somatic genomic variants in cancer. This community-based project highlights the need for cooperative efforts to curate clinical interpretations of somatic variants for robust practice of precision oncology.