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| Gene | CDK12 |
| Variant | H111fs |
| Impact List | frameshift |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | CDK12 H111fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 111 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). H111fs has not been biochemically characterized, however, due to the effects of other truncation mutations downstream of H111 (PMID: 24554720, PMID: 25712099), is predicted to lead to a loss of Cdk12 protein function. |
| Associated Drug Resistance | |
| Category Variants Paths |
CDK12 mutant CDK12 inact mut CDK12 H111fs |
| Transcript | NM_016507.4 |
| gDNA | chr17:g.(39462401_39462402) |
| cDNA | c.(331_330) |
| Protein | p.H111fs |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| XM_011524898 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024750.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436292.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524905 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024753 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| NM_015083 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524903.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| NM_016507.4 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524896 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436263.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436265.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436281.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524900 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_005257458.4 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024752 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024749.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024751 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524903 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436258.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524907 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524893.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524895 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524893 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436289.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436287.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436264.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436257.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024749 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436253.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436274.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436262.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024748.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436259.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524894.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436288.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024753.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| NM_016507.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436278.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024745 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436267.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524892.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024747 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436266.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436269.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436286.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024746 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436268.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436290.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524898.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524894.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436256.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524895.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524907.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436291.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_024450801.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436277.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524893.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524897 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436282.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436273.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436272.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524902 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436270.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524900.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524895.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436280.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524901.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436260.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024748 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524896.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524907.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436283.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524905.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| NM_015083.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| NM_015083.4 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436285.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524894 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524906.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436276.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524901 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_005257458 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524899.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_005257456 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524897.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436255.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436279.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524898.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436261.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436275.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436284.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524899 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024751.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524906.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_005257456.4 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024744 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024747.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024750 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524897.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_047436293.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524906 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_005257456.5 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024753.3 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524892 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| NM_016507 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_011524902.2 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| XM_017024752.1 | chr17:g.(39462401_39462402) | c.(331_330) | p.H111fs | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| 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 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 | 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 | 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 | 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 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 |