Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.

Center for Familial Breast and Ovarian Cancer Center for Integrated Oncology Medical Faculty University of Cologne and University Hospital Cologne Cologne Germany

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Medical Genetics AGEL Laboratories AGEL Research and Training Institute Novy Jicin Czech Republic

Department of Medical Genetics University Hospital Olomouc Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

GENNET Prague Czech Republic

GHC Genetics Prague Czech Republic

Hospital Ceske Budejovice Ceske Budejovice Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic; BIOCEV 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic; Department of Biochemistry Faculty of Science Charles University Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic; Department of Genetics and Microbiology Faculty of Science Charles University Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic; Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic; Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic; Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague Czech Republic; Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Medical Genetics University Hospital Pilsen Pilsen Czech Republic

Pronatal Prague Czech Republic

Zobrazit více v PubMed

Zannini L., Delia D., Buscemi G. CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol. 2014;6:442–457. PubMed PMC

Hu C., Hart S.N., Gnanaolivu R., Huang H., Lee K.Y., Na J., et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384:440–451. PubMed PMC

Dorling L., Carvalho S., Allen J., Gonzalez-Neira A., Luccarini C. Wahlström C., et al. Breast cancer risk genes - association analysis in more than 113,000 women. N Engl J Med. 2021;384:428–439. PubMed PMC

Cybulski C., Gorski B., Huzarski T., Masojc B., Mierzejewski M., Debniak T., et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75:1131–1135. PubMed PMC

Ma X., Zhang B., Zheng W. Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Gut. 2014;63:326–336. PubMed PMC

Siolek M., Cybulski C., Gasior-Perczak D., Kowalik A., Kozak-Klonowska B., Kowalska A., et al. CHEK2 mutations and the risk of papillary thyroid cancer. International journal of cancer Journal international du cancer. 2015;137:548–552. PubMed

Wieme G., Kral J., Rosseel T., Zemankova P., Parton B., Vocka M., et al. Prevalence of germline pathogenic variants in cancer predisposing genes in Czech and Belgian pancreatic cancer patients. Cancers. 2021;13:4430. PubMed PMC

Zlowocka-Perlowska E., Narod S.A., Cybulski C. CHEK2 alleles predispose to renal cancer in Poland. JAMA Oncol. 2019;5:576. PubMed

Havranek O., Kleiblova P., Hojny J., Lhota F., Soucek P., Trneny M., et al. Association of germline CHEK2 gene variants with risk and prognosis of non-hodgkin lymphoma. PLoS One. 2015;10 PubMed PMC

Stolarova L., Kleiblova P., Janatova M., Soukupova J., Zemankova P., Macurek L., et al. CHEK2 germline variants in cancer predisposition: stalemate rather than checkmate. Cells. 2020;9:2675. PubMed PMC

Sutcliffe E.G., Stettner A.R., Miller S.A., Solomon S.R., Marshall M.L., Roberts M.E., et al. Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. Cancer Genet. 2020;246–247:12–17. PubMed

Rainville I., Hatcher S., Rosenthal E., Larson K., Bernhisel R., Meek S., et al. High risk of breast cancer in women with biallelic pathogenic variants in CHEK2. Breast Cancer Res Treat. 2020;180:503–509. PubMed PMC

Stolarova L., Kleiblova P., Zemankova P., Stastna B., Janatova M., Soukupova J., et al. ENIGMA CHEK2gether project: a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk. Clin Cancer Res. 2023;29:3037–3050. PubMed PMC

Soukupova J., Zemankova P., Kleiblova P., Janatova M., Kleibl Z. [CZECANCA: Czech CAncer paNel for clinical application-- design and optimization of the targeted sequencing panel for the identification of cancer susceptibility in high-risk individuals from the Czech republic] Klin Onkol. 2016;29(Suppl 1):S46–S54. PubMed

Soukupova J., Zemankova P., Lhotova K., Janatova M., Borecka M., Stolarova L., et al. Validation of CZECANCA (Czech CAncer paNel for Clinical Application) for targeted NGS-based analysis of hereditary cancer syndromes. PLoS One. 2018;13 PubMed PMC

Lhotova K., Stolarova L., Zemankova P., Vocka M., Janatova M., Borecka M., et al. Multigene panel germline testing of 1333 Czech patients with ovarian cancer. Cancers. 2020;12 PubMed PMC

Janatova M., Chvojka S., Machackova E., Soukupova J., Zemankova P., Nehasil P., et al. Classification of germline variants identified in cancer predisposition genetic testing - consensus of the CZECANCA consortium. Klin Onkol : casopis Ceske a Slovenske onkologicke spolecnosti. 2023;37:431–439. PubMed

Walker L.C., Lattimore V.L., Kvist A., Kleiblova P., Zemankova P., de Jong L., et al. Comprehensive assessment of BARD1 messenger ribonucleic acid splicing with implications for variant classification. Front Genet. 2019;10:1139. PubMed PMC

Kleiblova P., Cerna M., Zemankova P., Matejkova K., Nehasil P., Hojny J., et al. Vol. 70. Folia Biologica; 2024. Parallel DNA/RNA NGS using identical target enrichment panel in the analysis of hereditary cancer predisposition. in press. PubMed

Lepkes L., Kayali M., Blumcke B., Weber J., Suszynska M., Schmidt S., et al. Performance of in silico prediction tools for the detection of germline copy number variations in cancer predisposition genes in 4208 female index patients with familial breast and ovarian cancer. Cancers. 2021;13 PubMed PMC

Kleiblova P., Stolarova L., Krizova K., Lhota F., Hojny J., Zemankova P., et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. International journal of cancer Journal international du cancer. 2019;145:1782–1797. PubMed

Schwartz C.J., Khorsandi N., Blanco A., Mukhtar R.A., Chen Y.Y., Krings G. Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants. Breast Cancer Res Treat. 2024;204:171–179. PubMed PMC

Horackova K., Janatova M., Kleiblova P., Kleibl Z., Soukupova J. Early-onset ovarian cancer <30 Years: what do we know about its genetic predisposition? Int J Mol Sci. 2023;24 PubMed PMC

Sanoguera-Miralles L., Valenzuela-Palomo A., Bueno-Martínez E., Esteban-Sánchez A., Lorca V., Llinares-Burguet I., et al. Systematic minigene-based splicing analysis and tentative clinical classification of 52 CHEK2 splice-site variants. Clin Chem. 2024;70:319–338. PubMed

Walker L.C., Hoya M., Wiggins G.A.R., Lindy A., Vincent L.M., Parsons M.T., et al. Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: recommendations from the ClinGen SVI Splicing Subgroup. Am J Hum Genet. 2023;110:1046–1067. PubMed PMC

A comprehensive analysis of germline predisposition to early-onset ovarian cancer