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| Gene | CDK12 |
| Variant | E928fs |
| Impact List | frameshift |
| Protein Effect | loss of function |
| Gene Variant Descriptions | CDK12 E928fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 928 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). E928fs confers a loss of function to the Cdk12 protein as demonstrated by an inability to interact with CycK in vitro and reduced homologous recombination repair activity in cell culture (PMID: 25712099), and loss of kinase activity in an in vitro assay (PMID: 24554720). |
| Associated Drug Resistance | |
| Category Variants Paths |
CDK12 mutant CDK12 inact mut CDK12 E928fs |
| Transcript | NM_016507.4 |
| gDNA | chr17:g.(39515743_39515744) |
| cDNA | c.(2782_2781) |
| Protein | p.E928fs |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| XM_017024745 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524896 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524899.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436257.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436275.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_024450801.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524906.3 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524901.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024747 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436267.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436274.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436269.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524899 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524907 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| NM_015083.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436288.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524900.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_005257458.4 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024749.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524900 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524898 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524898.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| NM_016507.4 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024744 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524894 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| NM_016507.3 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436260.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524903.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024751.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524906 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| NM_015083 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024750 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436278.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024752 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524893 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524898.3 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024750.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436259.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524894.3 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024752.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436272.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436287.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024751 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436276.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436273.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524902.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524907.3 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024748 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524906.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| NM_016507 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| NM_015083.4 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436261.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524895.3 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_005257458 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436266.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524893.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524897.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024748.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024747.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524893.3 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436289.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436256.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524896.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524901 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436265.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436277.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524895 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524902 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524903 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524897.3 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024746 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524894.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524905 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436258.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524895.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524907.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436268.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524905.2 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_011524897 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436279.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_017024749 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436270.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| XM_047436255.1 | chr17:g.(39515743_39515744) | c.(2782_2781) | p.E928fs | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| CDK12 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 CDK12, with an HR of 0.66 (p=0.12) in patients with non-BRCA mutations treated with Talzenna (talazoparib) (PMID: 37285865; NCT03395197). | detail... 37285865 |
| CDK12 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 CDK12 mutation who have not been treated in the setting of castration-resistant prostate cancer (NCCN.org). | detail... |
| CDK12 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 CDK12 mutation presumed to be inactivating, with no confirmed radiographic responses in 10 evaluable patients and a PSA response in 1 patient with biallelic CDK12 alterations in the overall population of 15 patients, and a clinical benefit rate of 20% (3/15) at 6 months and 7.1% (1/14) at 12 months (PMID: 32086346; NCT02952534). | 32086346 |
| CDK12 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 CDK12 (NCCN.org). | detail... |
| CDK12 inact mut | prostate cancer | sensitive | Olaparib | Phase II | Actionable | In a Phase II trial (TOPARP-B), Lynparza (olaparib) treatment resulted in a composite overall response rate of 25.0% (5/20) and a RECIST objective response rate of 0% (0/18) in patients with castration-resistant prostate cancer harboring deleterious CDK12 mutations (PMID: 31806540; NCT01682772). | 31806540 |
| CDK12 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 0.74 in CDK12-mutant patients (PMID: 32343890; NCT02987543). | detail... 32343890 detail... |
| CDK12 inact mut | Advanced Solid Tumor | predicted - sensitive | RP-3500 | Case Reports/Case Series | Actionable | In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a response rate of 12% (13/113), clinical benefit rate (CBR) of 42% (47/113), and median progression-free survival (mPFS) of 15 weeks in solid tumor patients with inactivating mutations in DNA damage repair genes, including CDK12 with a CBR of 28.6% (2/7), and with a CBR of 75% and mPFS of 35 weeks in 20 ovarian cancer patients (PMID: 37277454; NCT04497116). | 37277454 |
| CDK12 mutant | prostate cancer | predicted - sensitive | unspecified PD-1 antibody | Case Reports/Case Series | Actionable | In a clinical study, 50% (2/4) of prostate cancer patients with mutant CDK12 responded to an unspecified checkpoint inhibitor immunotherapy and had a corresponding decrease in prostate specific antigen (PMID: 29906450). | 29906450 |