{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:18:11Z","timestamp":1785417491345,"version":"3.56.0"},"reference-count":68,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nationwide Foundation Pediatric Innovation Fund","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience of pediatric oncology patients with CHEK2 germline alterations, including clinical presentations and outcomes. Methods: Pediatric oncology patients with CHEK2 germline alterations were identified among those assessed by clinical or translational research at the Institute for Genomic Medicine at Nationwide Children\u2019s Hospital. A chart review of disease course was conducted on identified patients. Results: We identified 6 patients with germline CHEK2 variants from a cohort of 300 individuals, including 1 patient with concurrent presentation of Burkitt lymphoma and neuroblastoma, 3 patients with brain tumors, 1 patient with Ewing sarcoma, and 1 patient with myelodysplastic syndrome. Three patients had a family history of malignancies. Four patients were in remission; one was undergoing treatment; one patient had developed treatment-related meningiomas. We review prior data regarding CHEK2 variants in this population, challenges associated with variant interpretation, and genetic counseling for individuals with CHEK2 variants. Conclusions: CHEK2 germline loss-of-function alterations occur in patients with a variety of pediatric tumors. Larger multicenter studies will improve our understanding of the incidence, phenotype, and molecular biology of CHEK2 germline variants in pediatric cancers.<\/jats:p>","DOI":"10.3390\/cancers15061649","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T01:58:22Z","timestamp":1678240702000},"page":"1649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience"],"prefix":"10.3390","volume":"15","author":[{"given":"Eman","family":"Abdelghani","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology\/Blood and Marrow Transplantation, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Schieffer","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children\u2019s Hospital, Columbus, OH 43215, USA"},{"name":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA"},{"name":"Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine E.","family":"Cottrell","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children\u2019s Hospital, Columbus, OH 43215, USA"},{"name":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA"},{"name":"Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2597-1212","authenticated-orcid":false,"given":"Anthony","family":"Audino","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology\/Blood and Marrow Transplantation, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Zajo","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology\/Blood and Marrow Transplantation, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3766-3572","authenticated-orcid":false,"given":"Nilay","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology\/Blood and Marrow Transplantation, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/ng.2529","article-title":"The genetic landscape of high-risk neuroblastoma","volume":"45","author":"Pugh","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.cancergen.2014.03.002","article-title":"Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors","volume":"207","author":"Roth","year":"2014","journal-title":"Cancer Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"21840","DOI":"10.18632\/oncotarget.8187","article-title":"Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression","volume":"7","author":"Lasorsa","year":"2016","journal-title":"Oncotarget"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature25480","article-title":"The landscape of genomic alterations across childhood cancers","volume":"555","author":"Grobner","year":"2018","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1056\/NEJMoa1508054","article-title":"Germline Mutations in Predisposition Genes in Pediatric Cancer","volume":"373","author":"Zhang","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nature12981","article-title":"Realizing the promise of cancer predisposition genes","volume":"505","author":"Rahman","year":"2014","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1093\/neuonc\/noz108","article-title":"Germline genetic landscape of pediatric central nervous system tumors","volume":"21","author":"Muskens","year":"2019","journal-title":"Neuro Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41598-019-57080-9","article-title":"Challenges in reporting pathogenic\/potentially pathogenic variants in 94 cancer predisposing genes\u2014In pediatric patients screened with NGS panels","volume":"10","author":"Andreescu","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gargallo, P., Oltra, S., Y\u00e1\u00f1ez, Y., Juan-Ribelles, A., Calabria, I., Segura, V., L\u00e1zaro, M., Balaguer, J., Tormo, T., and Dolz, S. (2021). Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care. Cancers, 13.","DOI":"10.3390\/cancers13215339"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1001\/jamaoncol.2015.5699","article-title":"Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children with Solid Tumors","volume":"2","author":"Parsons","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Stolarova, L., Kleiblova, P., Janatova, M., Soukupova, J., Zemankova, P., Macurek, L., and Kleibl, Z. (2020). CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. Cells, 9.","DOI":"10.3390\/cells9122675"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/j.molcel.2009.09.007","article-title":"Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase","volume":"35","author":"Cai","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/gim.2017.96","article-title":"Racial\/ethnic differences in multiple-gene sequencing results for hereditary cancer risk","volume":"20","author":"Gupta","year":"2018","journal-title":"Genet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"31463","DOI":"10.1074\/jbc.274.44.31463","article-title":"Role of human Cds1 (Chk2) kinase in DNA damage checkpoint and its regulation by p53","volume":"274","author":"Tominaga","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1053\/j.gastro.2017.11.004","article-title":"Germline Genetic Features of Young Individuals with Colorectal Cancer","volume":"154","author":"Stoffel","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1086\/426403","article-title":"CHEK2 is a multiorgan cancer susceptibility gene","volume":"75","author":"Cybulski","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Havranek, O., Kleiblova, P., Hojny, J., Lhota, F., Soucek, P., Trneny, M., and Kleibl, Z. (2015). Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140819"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11060-005-5953-7","article-title":"CHEK2 mutations in primary glioblastomas","volume":"74","author":"Sallinen","year":"2005","journal-title":"J. Neuro-Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Stolarova, L., Jelinkova, S., Storchova, R., Machackova, E., Zemankova, P., Vocka, M., Kodet, O., Kral, J., Cerna, M., and Volkova, Z. (2020). Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes. Biomedicines, 8.","DOI":"10.3390\/biomedicines8100404"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1038\/ng.3940","article-title":"A Children\u2019s Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor","volume":"49","author":"Gadd","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1200\/PO.20.00218","article-title":"Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults with Rhabdomyosarcoma","volume":"5","author":"Kim","year":"2021","journal-title":"JCO Precis Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1530\/ERC-20-0464","article-title":"Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma","volume":"28","author":"Stenman","year":"2021","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_25","unstructured":"Van der Auwera, G.A., and O\u2019Connor, B.D. (2020). Genomics in the Cloud: Using Docker, GATK, and WDL in Terra, O\u2019Reilly Media. [1st ed.]."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nbt.2514","article-title":"Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples","volume":"31","author":"Cibulskis","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1101\/gr.129684.111","article-title":"VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing","volume":"22","author":"Koboldt","year":"2012","journal-title":"Genome Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1056\/NEJMoa1915315","article-title":"Rituximab for High-Risk, Mature B-Cell Non-Hodgkin\u2019s Lymphoma in Children","volume":"382","author":"Pillon","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1080\/10428190903040048","article-title":"Report on the first international workshop on interim-PET scan in lymphoma","volume":"50","author":"Meignan","year":"2009","journal-title":"Leuk. Lymphoma"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.ijrobp.2016.09.046","article-title":"Results of COG ACNS0331: A phase III trial of involved-field radiotherapy (IFRT) and low dose craniospinal irradiation (LD-CSI) with chemotherapy in average-risk medulloblastoma: A report from the children\u2019s oncology group","volume":"5","author":"Michalski","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_31","first-page":"598","article-title":"Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation","volume":"1","author":"Schwarz","year":"2003","journal-title":"Mol. Cancer Res. MCR"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1158\/0008-5472.CAN-21-1845","article-title":"Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk","volume":"82","author":"Boonen","year":"2022","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1200\/JCO.21.00358","article-title":"Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients with Nonmetastatic Ewing Sarcoma: A Children\u2019s Oncology Group Report","volume":"39","author":"Leavey","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/cncr.31770","article-title":"The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children\u2019s Oncology Group","volume":"125","author":"Malempati","year":"2019","journal-title":"Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5195","DOI":"10.1093\/emboj\/cdf506","article-title":"Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription","volume":"21","author":"Takai","year":"2002","journal-title":"EMBO J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s10549-022-06517-3","article-title":"Somatic loss of the remaining allele occurs approximately in half of CHEK2-driven breast cancers and is accompanied by a border-line increase of chromosomal instability","volume":"192","author":"Iyevleva","year":"2022","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"pkz027","DOI":"10.1093\/jncics\/pkz027","article-title":"The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers","volume":"3","author":"Mandelker","year":"2019","journal-title":"JNCI Cancer Spectr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1126\/science.1140735","article-title":"An oncogene-induced DNA damage model for cancer development","volume":"319","author":"Halazonetis","year":"2008","journal-title":"Science"},{"key":"ref_39","first-page":"85","article-title":"Aberrations of the CHK2 gene are rare in pediatric solid tumors","volume":"16","author":"Chen","year":"2005","journal-title":"Int. J. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4937","DOI":"10.1007\/s13277-014-1648-z","article-title":"Genetic association of CHEK2, GSTP1, and ERCC1 with glioblastoma in the Han Chinese population","volume":"35","author":"Dong","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1177\/1093526617743905","article-title":"Targeted Sequencing of Malignant Supratentorial Pediatric Brain Tumors Demonstrates a High Frequency of Clinically Relevant Mutations","volume":"21","author":"Cole","year":"2018","journal-title":"Pediatr. Dev. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1159\/000521621","article-title":"Cancer-Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan","volume":"100","author":"Fukushima","year":"2022","journal-title":"Oncology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1111\/bpa.12884","article-title":"Pediatric meningioma: A clinicopathologic and molecular study with potential grading implications","volume":"30","author":"Toland","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.ajhg.2022.04.007","article-title":"Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes","volume":"109","author":"Gillani","year":"2022","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1038\/s41467-020-16067-1","article-title":"Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors","volume":"11","author":"Akhavanfard","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.leukres.2018.05.013","article-title":"Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML","volume":"70","author":"Janiszewska","year":"2018","journal-title":"Leuk. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.hemonc.2019.11.004","article-title":"Epigenetic changes in FOXO3 and CHEK2 genes and their correlation with clinicopathological findings in myelodysplastic syndromes","volume":"13","author":"Sharifi","year":"2020","journal-title":"Hematol.\/Oncol. Stem Cell Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1111\/his.14188","article-title":"Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability","volume":"77","author":"Acosta","year":"2020","journal-title":"Histopathology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/s11899-022-00663-7","article-title":"Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies","volume":"17","author":"Stubbins","year":"2022","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1038\/s41467-019-08578-3","article-title":"Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma","volume":"10","author":"Lopez","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1182\/blood-2016-10-747303","article-title":"Tonic B-cell receptor signaling in diffuse large B-cell lymphoma","volume":"130","author":"Havranek","year":"2017","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1530\/EC-19-0069","article-title":"Somatic genetic alterations in a large cohort of pediatric thyroid nodules","volume":"8","author":"Pekova","year":"2019","journal-title":"Endocr. Connect."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"34079","DOI":"10.18632\/oncotarget.26123","article-title":"Genetic and epigenetic analyses guided by high resolution whole-genome SNP array reveals a possible role of CHEK2 in Wilms tumour susceptibility","volume":"9","author":"Ciceri","year":"2018","journal-title":"Oncotarget"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1093\/jnci\/djac196","article-title":"Somatic Inactivation of Breast Cancer Predisposition Genes in Tumours Associated with Pathogenic Germline Variants","volume":"115","author":"Lim","year":"2023","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"718689","DOI":"10.3389\/fgene.2022.718689","article-title":"The First Case Report of a Patient with Oligodendroglioma Harboring CHEK2 Germline Mutation","volume":"13","author":"Li","year":"2022","journal-title":"Front. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1158\/1078-0432.CCR-21-2096","article-title":"Pan-cancer Analysis of Homologous Recombination Repair-associated Gene Alterations and Genome-wide Loss-of-Heterozygosity Score","volume":"28","author":"Westphalen","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1593\/neo.111574","article-title":"Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma","volume":"14","author":"Yang","year":"2012","journal-title":"Neoplasia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1002\/humu.24110","article-title":"Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients","volume":"41","author":"Rofes","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_60","unstructured":"National Library of Medicine (2022, November 25). ClinVar Database, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1002\/ijc.23026","article-title":"Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts","volume":"121","author":"Bell","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.trecan.2022.04.009","article-title":"CHEK2 variants: Linking functional impact to cancer risk","volume":"8","author":"Boonen","year":"2022","journal-title":"Trends Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/humu.23728","article-title":"Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system","volume":"40","author":"Delimitsou","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.amjsurg.2018.08.008","article-title":"Factors predicting reclassification of variants of unknown significance","volume":"216","author":"Wright","year":"2018","journal-title":"Am. J. Surg."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.ajhg.2021.03.010","article-title":"Machine learning-based reclassification of germline variants of unknown significance: The RENOVO algorithm","volume":"108","author":"Favalli","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41436-018-0063-z","article-title":"The impact of variant classification on the clinical management of hereditary cancer syndromes","volume":"21","author":"Turner","year":"2019","journal-title":"Genet. Med."},{"key":"ref_67","unstructured":"NCCN (2022, December 14). Genetic\/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/genetics_bop.pdf."},{"key":"ref_68","unstructured":"NCCN (2022, December 14). Genetic\/Familial High-Risk Assessment: Colorectal. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/genetics_colon.pdf."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/6\/1649\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:50:32Z","timestamp":1760122232000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/6\/1649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,8]]},"references-count":68,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["cancers15061649"],"URL":"https:\/\/doi.org\/10.3390\/cancers15061649","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,8]]}}}