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| Gene | CHEK2 |
| Variant | N185fs |
| Impact List | frameshift |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | CHEK2 N185fs results in a change in the amino acid sequence of the Chek2 protein beginning at aa 185 of 543, likely resulting in premature truncation of the functional protein (UniProt.org). N185fs has not been characterized, however, due to the effects of other truncation mutations downstream of N185 resulting in disruption of the protein kinase domain (PMID: 11053450, PMID: 16982735, PMID: 31050813), is predicted to lead to a loss of Chek2 protein function. |
| Associated Drug Resistance | |
| Category Variants Paths |
CHEK2 mutant CHEK2 inact mut CHEK2 N185fs |
| Transcript | NM_007194.4 |
| gDNA | chr22:g.(28725016_28725017) |
| cDNA | c.(553_552) |
| Protein | p.N185fs |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_145862.2 | chr22:g.(28725016_28725017) | c.(553_552) | p.N185fs | RefSeq | GRCh38/hg38 |
| NM_007194.3 | chr22:g.(28725016_28725017) | c.(553_552) | p.N185fs | RefSeq | GRCh38/hg38 |
| XM_047441106.1 | chr22:g.(28725109_28725110) | c.(553_552) | p.N185fs | RefSeq | GRCh38/hg38 |
| NM_145862.2 | chr22:g.(28725016_28725017) | c.(553_552) | p.N185fs | RefSeq | GRCh38/hg38 |
| XM_047441104.1 | chr22:g.(28725109_28725110) | c.(553_552) | p.N185fs | RefSeq | GRCh38/hg38 |
| NM_007194.4 | chr22:g.(28725016_28725017) | c.(553_552) | p.N185fs | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| 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 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 | 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 | 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 | 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 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 |
| 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 | 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 | prostate cancer | not applicable | N/A | Guideline | Risk Factor | Germline CHEK2 mutations are associated with increased risk of developing prostate cancer (NCCN.org). | detail... |