ArticleAmerican journal of human genetics2024
A missense variant effect map for the human tumor-suppressor protein CHK2.
Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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The trial behind it
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Who cites it
12 citing papers in PubMed.
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- VEFill: accurate and generalizable deep mutational scanning score imputation across protein domains.Molecular systems biology · 2026Article
- Integrated proteomic and single-nucleus transcriptomic profiling identifies prognostic markers and therapeutic targets in glioblastoma.Discover oncology · 2026Article
- Determining the intra-residue correlation of missense variant impact using MAVE scores: implications for the ACMG/AMP PM5 criterion for DNA variant classification.Genome medicine · 2026Article
- A scalable approach to resolving variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- MaveMD: A functional data resource for genomic medicine.medRxiv : the preprint server for health sciences · 2025Article
- acmgscaler: an R package and Colab for standardized gene-level variant effect score calibration within the ACMG/AMP framework.Bioinformatics (Oxford, England) · 2025Article
- Variant scoring tools for deep mutational scanning.Molecular systems biology · 2025Review
- Saturation mapping of MUTYH variant effects using DNA repair reporters.American journal of human genetics · 2025Article
- VEFill: a model for accurate and generalizable deep mutational scanning score imputation across protein domains.bioRxiv : the preprint server for biology · 2025Article
- Complementary Roles of Structure and Variant Effect Predictors in RyR1 Clinical Interpretation.Human mutation · 2025Article
Corrections and comments
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Authors and funding
19 authors.
Funding
Abstract
The tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers. Over 90% of clinical germline CHEK2 missense variants are classified as variants of uncertain significance, complicating diagnosis of CHK2-dependent cancer. We therefore sought to test the functional impact of all possible missense variants in CHK2. Using a scalable multiplexed assay based on the ability of human CHK2 to complement DNA sensitivity of Saccharomyces cerevisiae cells lacking the CHEK2 ortholog, RAD53, we generated a systematic "missense variant effect map" for CHEK2 missense variation. The map reflects known biochemical features of CHK2 while offering new biological insights. It also provides strong evidence toward pathogenicity for some clinical missense variants and supporting evidence toward benignity for others. Overall, this comprehensive missense variant effect map contributes to understanding of both known and yet-to-be-observed CHK2 variants.
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