ArticleCancer research2022
Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 2 of them syntheses that pooled it.
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Who cites it
36 citing papers in PubMed, 2 syntheses or guidelines pooled it, 54 citations in OpenAlex.
- Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine : official journal of the American College of Medical Genetics · 2023Guideline
- ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Pooled it
- Hereditary breast cancer: emerging roles of non-coding RNAs.Hereditas · 2026Review
- CHK2 regulates MUS81-dependent DSBs in response to replication stress and BRCA2 deficiency.Nucleic acids research · 2026Article
- Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk.Nature communications · 2026Article
- Discriminating activating, deactivating and resistance variants in protein kinases.Genome medicine · 2025Article
- Different Mechanisms in Doxorubicin-Induced Neurotoxicity: Impact of BRCA Mutations.International journal of molecular sciences · 2025Review
- Case Report: A rare pediatric case of B-cell lymphoblastic lymphoma presenting as an isolated renal mass withFrontiers in pediatrics · 2025Article
- A missense variant effect map for the human tumor-suppressor protein CHK2.American journal of human genetics · 2024Article
- Molecular and In Silico Analysis of theCancers · 2024Article
- Germline Variant Spectrum in Southern Italian High-Risk Hereditary Breast Cancer Patients: Insights from Multi-Gene Panel Testing.Current issues in molecular biology · 2024Article
- Germline Variants in Proto-Oncogenes and Tumor Suppressor Genes in Women with Cervical Cancer.Biomedicines · 2024Article
- Protein-truncating and rare missense variants inJournal of medical genetics · 2024Article
- Increased Prevalence of Germline Pathogenic CHEK2 Variants in Individuals With Pituitary Adenomas.The Journal of clinical endocrinology and metabolism · 2024Article
- Comprehensive analysis of the functional impact of single nucleotide variants of human CHEK2.PLoS genetics · 2024Article
- Article
- Rethinking the use of germline CHEK2 mutation as a marker for PARP inhibitor sensitivity.JNCI cancer spectrum · 2024Article
- Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients.Journal of personalized medicine · 2024Article
- Machine learning reveals diverse cell death patterns in lung adenocarcinoma prognosis and therapy.NPJ precision oncology · 2024Article
- Review
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
Abstract
Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally and clinically. Here we describe a mouse embryonic stem (mES) cell-based system to quantitatively determine the functional impact of 50 missense VUS in human CHEK2. By assessing the activity of human CHK2 to phosphorylate one of its main targets, Kap1, in Chek2 knockout mES cells, 31 missense VUS in CHEK2 were found to impair protein function to a similar extent as truncating variants, while 9 CHEK2 missense VUS resulted in intermediate functional defects. Mechanistically, most VUS impaired CHK2 kinase function by causing protein instability or by impairing activation through (auto)phosphorylation. Quantitative results showed that the degree of CHK2 kinase dysfunction correlates with an increased risk for breast cancer. Both damaging CHEK2 variants as a group [OR 2.23; 95% confidence interval (CI), 1.62-3.07; P < 0.0001] and intermediate variants (OR 1.63; 95% CI, 1.21-2.20; P = 0.0014) were associated with an increased breast cancer risk, while functional variants did not show this association (OR 1.13; 95% CI, 0.87-1.46; P = 0.378). Finally, a damaging VUS in CHEK2, c.486A>G/p.D162G, was also identified, which cosegregated with familial prostate cancer. Altogether, these functional assays efficiently and reliably identified VUS in CHEK2 that associate with cancer. SIGNIFICANCE: Quantitative assessment of the functional consequences of CHEK2 variants of uncertain significance identifies damaging variants associated with increased cancer risk, which may aid in the clinical management of patients and carriers.
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