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Gene CHEK2
Variant K373E
Impact List missense
Protein Effect loss of function
Gene Variant Descriptions CHEK2 K373E lies within the protein kinase domain of the Chek2 protein (UniProt.org). K373E results in decreased Chek2 kinase activity and autophosphorylation, and fails to inhibit cell proliferation or promote survival following radiation in cell culture (PMID: 27716909).
Associated Drug Resistance
Category Variants Paths

CHEK2 mutant CHEK2 inact mut CHEK2 K373E

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Transcript NM_007194.4
gDNA chr22:g.28695852T>C
cDNA c.1117A>G
Protein p.K373E
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_007194 chr22:g.28695852T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529844 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529840.3 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529840 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529840.4 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529844.3 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529839 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
NM_007194.4 chr22:g.28695852T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
NM_007194.3 chr22:g.28695852T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529844.2 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529839.3 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38
XM_011529839.2 chr22:g.28699888T>C c.1117A>G p.K373E RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CHEK2 inact mut prostate cancer no benefit Rucaparib Phase II Actionable In a Phase II trial (TRITON2), activity of Rubraca (rucaparib) was limited in the cohort of patients with metastatic castrate-resistant prostate cancer harboring a CHEK2 mutation presumed to be inactivating, with a radiographic partial response in 1 patient who had a co-occurring ATM alteration out of 9 evaluable patients, and PSA response rate of 16.7% (2/12), and a clinical benefit rate of 37.5% (3/8) at 6 months, with no patients remaining on treatment at 12 months (PMID: 32086346; NCT02952534). 32086346
CHEK2 inact mut prostate cancer predicted - sensitive Abiraterone + Niraparib + Prednisone Phase III Actionable In a Phase III trial (MAGNITUDE), Zejula (niraparib) in combination with Zytiga (abiraterone) and Adasone (prednisone) (AAP) improved radiographic progression-free survival (HR 0.64) compared to placebo and AAP in patients with metastatic castration-resistant prostate cancer harboring inactivating mutations in the homologous recombination repair (HRR)-associated genes (CHEK2 or HDAC2), with a HR of 0.66 in patients with CHEK2 mutations (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 5020; NCT03748641). detail...
CHEK2 inact mut prostate cancer sensitive Enzalutamide + Talazoparib FDA approved Actionable In a Phase III trial (TALAPRO-2) that supported FDA approval, Talzenna (talazoparib) plus Xtandi (enzalutamide) improved median radiographic progression-free survival compared to enzalutamide plus placebo (27.9 vs 16.4 mo, HR 0.46, p=0.0003) in patients with metastatic castration-resistant prostate cancer harboring deficient homologous recombination repair genes including CHEK2, with an HR of 0.66 (p=0.12) in patients with non-BRCA mutations treated with Talzenna (talazoparib) (PMID: 37285865; NCT03395197). detail... 37285865
CHEK2 inact mut prostate cancer sensitive Enzalutamide + Talazoparib Guideline Actionable Talzenna (talazoparib) plus Xtandi (enzalutamide) is included in guidelines as systemic therapy for patients with metastatic castration-resistant prostate cancer harboring a pathogenic germline or somatic CHEK2 mutation who have not been treated in the setting of castration-resistant prostate cancer (NCCN.org). detail...
CHEK2 inact mut prostate cancer no benefit unspecified PARP inhibitor Clinical Study - Meta-analysis Actionable In a combined analysis of 6 clinical trials, PARP inhibitor therapy did not benefit patients with metastatic castration-resistant prostate cancer harboring CHEK2 mutations compared to placebo, with an HR of 1.06 (14 vs 18 mo) for radiographic progression-free survival and 1.53 (26 vs 34 mo) for overall survival when combined with AR pathway inhibitors, and an objective response rate of 0% (0/17) as monotherapy (PMID: 38484203; NCT02987543, NCT03732820, NCT03395197, NCT03748641, NCT02952534, NCT03148795). 38484203
CHEK2 inact mut prostate cancer sensitive Olaparib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (PROfound) that supported FDA approval, Lynparza (olaparib) improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in metastatic castration-resistant prostate cancer patients harboring deleterious or suspected deleterious mutations in homologous recombination repair genes who progressed on hormone therapy, HR for progression or death was 0.87 in CHEK2-mutant patients (PMID: 32343890; NCT02987543). detail... detail... 32343890
CHEK2 inact mut prostate cancer sensitive Olaparib Guideline Actionable Lynparza (olaparib) is included in guidelines as second-line therapy post androgen receptor-directed therapy for patients with metastatic castration-resistant prostate cancer harboring pathogenic mutations in CHEK2 (NCCN.org). detail...
CHEK2 mutant breast cancer not applicable N/A Guideline Risk Factor Germline CHEK2 mutations are associated with increased risk of developing breast cancer (NCCN.org). detail...
CHEK2 mutant Advanced Solid Tumor no benefit Olaparib Phase II Actionable In a Phase II trial, Lynparza (olaparib) treatment did not demonstrate clinical activity in patients with advanced solid tumors harboring ATM (n=13) or CHEK2 (n=14) mutations (Ann Oncol (2023) 34 (suppl_2): S242; NCT03967938). detail...
CHEK2 mutant prostate cancer not applicable N/A Guideline Risk Factor Germline CHEK2 mutations are associated with increased risk of developing prostate cancer (NCCN.org). detail...
CHEK2 mutant breast cancer no benefit Olaparib Case Reports/Case Series Actionable In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment did not result in an objective response in 7 patients with metastatic breast cancer harboring only germline mutations in CHEK2 (PMID: 33119476; NCT03344965). 33119476