CHEK2 (O96017) variants and mutations

CHEK2 (also known as O96017) is a human protein-coding gene encoding a serine/threonine-protein kinase Chk2 protein. It propagates DNA-damage checkpoint signals to proteins controlling cell-cycle arrest, repair, and apoptosis. Germline loss-of-function variants confer moderate cancer susceptibility, especially for breast cancer, while risk estimates depend on the specific allele and family context. This analysis covers 2,783 CHEK2 variants and mutations. Of these, 13% have pathogenic or likely pathogenic clinical classifications, 58% have computational variant effect predictions from REVEL and MutPred, and 30% have population-specific frequency data. Disease context includes breast cancer, Hereditary breast cancer, and hereditary breast carcinoma. Example CHEK2 variants include M1?, M1F, and M1I.

Variant analysis overview

Gene: CHEK2
Protein: O96017
UniProt accession: O96017
Organism: Homo sapiens
Variants analyzed: 2783
Variant scope: all variants
Completed: 2026-08-10

Variant and mutation evidence

Variant composition: 2,687 unspecified-consequence records; 1 stop lost; 49 synonymous variants; 21 missense variants; 12 frameshift variants; 7 in-frame deletions; 2 splice-region variants; 1 stop-gained variants; 3 substitution
Clinical classifications: 351 pathogenic or likely pathogenic; 227 benign or likely benign; 1,865 uncertain-significance; 15 other clinical labels.
Computational signals: 182 REVEL high-risk; 162 MutPred high-risk.
Variant classes: 2,537 missense; 49 synonymous; 192 truncating or splice.
Prediction scores: 1,626 variants have prediction scores (59% of the analyzed set).
Literature: 24 publications are represented in the literature summary.

Clinical, disease, and population context

Clinical evidence: 8 records have expert-only or criteria-backed evidence.
Clinical annotations: 2,459 variants have clinical annotations.
Population evidence: 1,062 variants have population-frequency evidence.
Disease context: 25 disease associations are represented. Top associations: breast cancer, Hereditary breast cancer, hereditary breast carcinoma, prostate cancer, Familial prostate cancer, CHEK2-related cancer predisposition, Inherited cancer-predisposing syndrome, hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, might influence susceptibility to breast cancer, TPDS4, confers a moderate risk of breast cancer.

Protein structure and variant hotspots

Protein features: 2 domains; 5 binding sites; 7 post-translational modification sites.
Ancestry evidence: 834 variants have ancestry-specific frequency data.
Structural context: 1,668 variants have structural context.
PTM context: 30 variants overlap post-translational modification sites.
3D hotspots: 8 hotspot clusters were identified. Clusters at residues 287-301 (tolerant, 13 variants); residues 213-296 (tolerant, 14 variants); residues 273-409 (intolerant, 39 variants).
Allosteric analysis: 8 functional sites were identified.
gnomAD gene constraint: pLI 0.00 (tolerant of loss-of-function variation); LOEUF 1.03; missense Z-score -0.24.

Data sources

Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.

Notable CHEK2 variants

Examples include M1?, M1F, M1I, M1K, M1L, M1V, S2A, S2C. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.

CHEK2 analysis run — CHEK2 (2,783 variants) — completed 2026-08-10