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| Gene | ATM |
| Variant | S2592C |
| Impact List | missense |
| Protein Effect | loss of function |
| Gene Variant Descriptions | ATM S2592C does not lie within any known functional domains of the Atm protein (UniProt.org). S2592C confers a loss of function to the Atm protein as demonstrated by loss of kinase activity in an in vitro assay and cultured cells, and increased radiosensitivity and radiation-induced chromosome aberrations in cultured cells (PMID: 11805335). |
| Associated Drug Resistance | |
| Category Variants Paths |
ATM mutant ATM inact mut ATM S2592C |
| Transcript | NM_000051.4 |
| gDNA | chr11:g.108332024C>G |
| cDNA | c.7775C>G |
| Protein | p.S2592C |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| XM_011542843.3 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| NM_000051.3 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_005271562.6 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_011542840.4 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_047426976.1 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_005271562.5 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_047426975.1 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_017017790.2 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_011542840.3 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| NM_000051.4 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| NM_001351834.1 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_017017789.2 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_017017790.3 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_006718843.4 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| NM_001351834.2 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_011542843.2 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| XM_006718843.5 | chr11:g.108332024C>G | c.7775C>G | p.S2592C | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| ATM inact mut | lymphoid leukemia | sensitive | Olaparib | Preclinical - Patient cell culture | Actionable | In a preclinical study, lymphoblastoid cell lines with ATM inactivation derived from ataxia-telangiectasia patients demonstrated increased sensitivity to Lynparza (olaparib) in culture, compared to ATM wild-type cell lines (PMID: 20739657). | 20739657 |
| ATM inact mut | mantle cell lymphoma | sensitive | Olaparib + Valproic acid | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Lynparza (olaparib) and valproic acid worked synergistically to inhibit growth of a mantle cell lymphoma cell line harboring an ATM inactivating mutation in culture (PMID: 20739657). | 20739657 |
| ATM inact mut | Advanced Solid Tumor | no benefit | Avelumab + Talazoparib | Phase II | Actionable | In a Phase II trial (JAVELIN), Talzenna (talazoparib) and Bavencio (avelumab) combination therapy did not meet the prespecified futility requirement with a confirmed objective response rate of 4.9% (2/41, 2 partial responses) in patients with advanced solid tumors harboring ATM inactivating mutations, and subsequently, enrollment to the cohort was discontinued (PMID: 36394867; NCT03565991). | 36394867 |
| ATM inact mut | mantle cell lymphoma | sensitive | Bendamustine + Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, Lynparza (olaparib) sensitized a mantle cell lymphoma cell line harboring an ATM inactivating mutation to Treanda (bendamustine) in cell culture, resulting in growth inhibition (PMID: 20739657). | 20739657 |
| ATM inact mut | Advanced Solid Tumor | predicted - sensitive | Radiotherapy + RP-3500 | Case Reports/Case Series | Actionable | In a Phase I trial, the addition of RP-3500 to radiotherapy treatment resulted in metabolic complete responses in two patients with advanced solid tumors harboring ATM inactivating mutations (Cancer Res (2024) 84 (1_Supplement): A002, NCT05566574). | detail... |
| ATM inact mut | chronic lymphocytic leukemia | sensitive | Olaparib | Preclinical - Patient cell culture | Actionable | In a preclinical study, patient-derived chronic lymphocytic leukemia cells with inactivating mutations in ATM, that had been induced to proliferate in culture, demonstrated increased sensitivity to growth inhibition by Lynparza (olaparib) compared to ATM wild-type cells (PMID: 20739657). | 20739657 |
| ATM 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 36.8% (7/19) and a RECIST objective response rate of 8.3% (1/12) in patients with castration-resistant prostate cancer harboring deleterious ATM mutations (PMID: 31806540; NCT01682772). | 31806540 |
| ATM 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 ATM (NCCN.org). | detail... |
| ATM 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 progression-free survival (7.4 vs 3.6 mo, HR 0.34, p<0.001), objective response rate (33% vs 2%, OR 20.86, p<0.001), and median overall survival (18.5 vs 15.1 mo, HR 0.64, p=0.02) compared to control in metastatic castration-resistant prostate cancer patients harboring deleterious or suspected deleterious BRCA or ATM mutations, HR for progression or death was 1.04 in ATM-mutant patients (PMID: 32343890; NCT02987543). | detail... 32343890 detail... |
| ATM inact mut | transitional cell carcinoma | predicted - sensitive | Durvalumab + Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial (BAYOU), Lynparza (olaparib) and Imfinzi (durvalumab) improved median progression-free survival (5.6 vs 1.8 mo, HR 0.18) compared to Imfinzi (durvalumab) and placebo in a subgroup of patients with metastatic urothelial carcinoma harboring inactivating mutations in DNA damage repair genes (n=17), with 8.5% of the tumors harboring ATM inactivating mutations (PMID: 35737919; NCT03459846). | 35737919 |
| ATM inact mut | mantle cell lymphoma | sensitive | Fludarabine + Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, Lynparza (olaparib) sensitized a mantle cell lymphoma cell line harboring an ATM inactivating mutation to Fludara (fludarabine) in cell culture, resulting in decreased cell survival (PMID: 20739657). | 20739657 |
| ATM inact mut | prostate cancer | sensitive | Abiraterone + Olaparib + Prednisone | Case Reports/Case Series | Actionable | In a Phase II trial (BRCAAway), Zytiga (abiraterone), Adason (prednisone), and Lynparza (olaparib) first-line combination treatment led to an objective response rate of 33% (7/21) and improved median progression-free survival compared to olaparib (39 mo vs 14 mo, HR=0.37) or the combination of abiraterone and prednisone (39 mo vs 8.6 mo, HR=0.33) in patients with metastatic castration-resistant prostate cancer harboring BRCA1 (n=3), BRCA2 (n=46) or ATM (n=11) mutations (PMID: 39115414; NCT03012321). | 39115414 |
| ATM 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 ATM mutations compared to placebo, with an HR of 1.05 (19 vs 19 mo) for radiographic progression-free survival and 1.18 (33 vs 33 mo) for overall survival when combined with AR pathway inhibitors, and an objective response rate of 7% (5/70) as monotherapy (PMID: 38484203; NCT02987543, NCT03732820, NCT03395197, NCT03748641, NCT02952534, NCT03148795). | 38484203 |
| ATM inact mut | Advanced Solid Tumor | predicted - sensitive | Radiotherapy | Clinical Study | Actionable | In a clinical study, treatment with radiotherapy resulted in greater therapeutic efficacy in advanced solid tumor patients harboring an ATM inactivating mutation (n=177) compared to those who harbored an ATM variant of unknown significance (n=180), demonstrating a significantly decreased 2-year cumulative incidence of irradiated progression, 13.2% versus 27.5% (p=0.001), respectively, and the greatest clinical benefit was observed in tumors with bi-allelic ATM inactivating mutations (PMID: 32726432). | 32726432 |
| ATM inact mut | Advanced Solid Tumor | predicted - sensitive | Ceralasertib + Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial (OLAPCO), Ceralasertib (AZD6738) and Lynparza (olaparib) combination treatment resulted in an overall response rate of 20% (1/5) and a clinical benefit rate of 40% (2/5) in patients with advanced solid tumors harboring ATM inactivating mutations, including a durable complete response in a patient with breast cancer and a durable stable disease in a patient with adenoid cystic carcinoma of minor salivary gland (PMID: 34527850; NCT02576444). | 34527850 |
| ATM inact mut | Advanced Solid Tumor | sensitive | E7449 | Preclinical | Actionable | In a preclinical study, E7449 inhibited proliferation of a ATM-deficient cell line in culture, which demonstrated increased sensitivity compared to cells without DNA repair pathway mutations (PMID: 26513298). | 26513298 |
| ATM inact mut | prostate cancer | no benefit | Ceralasertib | Phase II | Actionable | In a Phase IIa trial (PLANETTE), Ceralasertib (AZD6738) treatment demonstrated manageable safety but limited efficacy in patients with metastatic castration-resistant prostate cancer harboring ATM mutations and/or ATM loss (n=15), with a composite response rate of 7.7% (1/13) in patients with confirmed ATM mutations (Cancer Res (2024) 84 (7_Supplement): CT222; NCT04564027). | detail... |
| ATM inact mut | lung non-small cell carcinoma | predicted - sensitive | RP-3500 | Case Reports/Case Series | Actionable | In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a partial response after 37 weeks of treatment in a patient with advanced non-small cell lung cancer harboring germline biallelic ATM inactivation (PMID: 37277454; NCT04497116). | 37277454 |
| ATM inact mut | Advanced Solid Tumor | predicted - sensitive | Durvalumab + Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial, treatment with the combination of Lynparza (olaparib) and Imfinzi (durvalumab) led to a 6-month progression-free survival (PFS) rate of 35%, objective tumor response (OTR) rate of 19% (3/16, all partial responses (PR)), and median PFS of 3.7mo in advanced solid tumor patients harboring BRCA1/2 mutations and a 6-month PFS rate of 38%, OTR rate of 9% (3/32, 1 complete, 2 PR), and median PFS of 3.6mo with other HRR alterations, including ATM (n=9) and CHEK2 (n=3) (PMID: 37365284). | 37365284 |
| ATM inact mut | Advanced Solid Tumor | predicted - sensitive | RP-3500 | Phase Ib/II | Actionable | In a Phase I/II trial (TRESR), RP-3500 treatment resulted in an overall response rate (ORR) of 15% (7/46) and clinical benefit rate of 48% (22/46) in advanced solid tumor patients with ATM inactivation, an ORR of 18% (5/28) with germline ATM loss of function (LOF) mutations, and an ORR of 13% (2/15) with somatic ATM LOF mutations, with benefit in patients with non-small cell lung (n=2), bile duct (3/4), colorectal (3/6), and prostate (4/8) cancers (Ann Oncol (2024) 35 (Suppl_2): S496; NCT04497116). | detail... |
| ATM inact mut | pancreatic cancer | predicted - sensitive | RP-3500 | Case Reports/Case Series | Actionable | In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a partial response at week 54 in a patient with advanced pancreatic cancer harboring a germline ATM frameshift mutation (PMID: 37277454; NCT04497116). | 37277454 |
| ATM inact mut | Advanced Solid Tumor | no benefit | Ceralasertib | Phase II | Actionable | In a Phase IIa trial (PLANETTE), Ceralasertib (AZD6738) treatment demonstrated manageable safety but limited efficacy in patients with advanced solid tumors excluding non-small cell lung cancer harboring ATM mutations and/or loss of ATM protein expression (n=30), resulting in an objective response rate of 7.1% (2/28, 1 complete and 1 partial response) (Cancer Res (2024) 84 (7_Supplement): CT222; NCT04564027). | detail... |
| ATM inact mut | lung non-small cell carcinoma | predicted - sensitive | Ceralasertib + Durvalumab | Phase II | Actionable | In a Phase II trial (HUDSON), treatment with the combination of Imfinzi (durvalumab) and Ceralasertib (AZD6738) demonstrated efficacy in patients with advanced non-small cell lung cancer harboring inactivating ATM mutations, with an objective response rate of 26.1% (6/23, all partial responses), a median progression-free survival of 8.4 months, and a median overall survival of 22.8 months (PMID: 38351187; NCT03334617). | 38351187 |
| ATM inact mut | Advanced Solid Tumor | sensitive | Irinotecan + Rucaparib | Phase I | Actionable | In a Phase I trial, Rubraca (rucaparib) and Camptosar (irinotecan) combination therapy was well tolerated and resulted in a clinical benefit rate of 35% (6/17, 2 partial responses, 4 stable diseases over 6 months) in patients with advanced solid tumors harboring BRCA1 (n=3), BRCA2 (n=4), PALB2 (n=1), or ATM (n=11) mutations, including partial responses in a patient with PALB2-mutated peritoneal carcinoma and in a patient with ATM-mutated small bowel carcinoma (PMID: 38865673; NCT03318445). | 38865673 |
| ATM inact mut | Advanced Solid Tumor | no benefit | Ipilimumab + Nivolumab | Phase II | Actionable | In a Phase II trial (TAPUR), Opdivo (nivolumab) and Yervoy (ipilimumab) combination treatment did not meet predetermined efficacy criteria in patients with advanced solid tumors harboring ATM mutations, resulting in an objective response rate of 14% (4/29, 1 complete and 3 partial responses), a disease control rate of 24% (7/29), with stable disease of at least 16 weeks in 3 patients, a median progression-free survival of 9 weeks, and median overall survival of 28 weeks (PMID: 38039429; NCT02693535). | 38039429 |
| ATM inact mut | Advanced Solid Tumor | sensitive | Veliparib | Preclinical - Cell culture | Actionable | In a preclinical study, an ATM-deficient cell line demonstrated increased sensitivity to Veliparib (ABT-888) compared to an ATM-reconstituted cell line, in culture (PMID: 21300883). | 21300883 |
| ATM inact mut | neuroendocrine carcinoma | predicted - sensitive | Durvalumab + Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial, treatment with the combination of Lynparza (olaparib) and Imfinzi (durvalumab) resulted in a partial response in a patient with a neuroendocrine carcinoma harboring an ATM inactivating mutation (PMID: 37365284). | 37365284 |
| ATM inact mut | mantle cell lymphoma | sensitive | Olaparib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a mantle cell lymphoma cell line with ATM inactivation demonstrated sensitivity to Lynparza (olaparib) in culture and in xenograft models (PMID: 20739657). | 20739657 |
| ATM inact mut | Advanced Solid Tumor | predicted - sensitive | Elimusertib | Phase I | Actionable | In a Phase I trial, Elimusertib (BAY1895344) treatment was tolerated and resulted in an objective response rate of 36.4% (4/11, all partial responses) and a disease control rate of 63.6% (7/11) in patients with advanced solid tumors harboring ATM inactivating mutations and/or ATM protein expression loss (PMID: 32988960; NCT03188965). | 32988960 |
| ATM 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 ATM, with an HR of 0.66 (p=0.12) in patients with non-BRCA mutations treated with Talzenna (talazoparib) (PMID: 37285865; NCT03395197). | detail... 37285865 |
| ATM 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 ATM mutation who have not been treated in the setting of castration-resistant prostate cancer (NCCN.org). | detail... |
| ATM inact mut | prostate cancer | no benefit | Rucaparib | Phase III | Actionable | In a Phase III trial (TRITON3), Rubraca (rucaparib) treatment demonstrated limited efficacy compared to control treatment with Taxotere (docetaxel) in patients with metastatic castration-resistant prostate cancer harboring deleterious ATM mutations, with a median imaging-based progression-free survival of 8.1 months vs. 6.8 months (HR=0.95), a median overall survival of 21.1 months vs. 21.7 months of patients (PMID: 36795891; NCT02975934). | 36795891 |
| ATM 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 an ATM mutation presumed to be inactivating, with a radiographic response rate of 10.5% (2/19, including 1 patient with co-occurring CHEK2 alteration) and PSA response rate of 4.1% (2/49), and no radiographic responses in 11 patients with biallelic alterations in ATM or 11 patients with germline ATM alterations (PMID: 32086346; NCT02952534). | 32086346 |
| ATM inact mut | invasive ductal carcinoma | predicted - sensitive | Durvalumab + Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial, treatment with the combination of Lynparza (olaparib) and Imfinzi (durvalumab) resulted in a partial response in a patient with invasive ductal carcinoma harboring an ATM inactivating mutation (PMID: 37365284). | 37365284 |
| ATM mutant | prostate cancer | sensitive | Olaparib | Phase II | Actionable | In a Phase II clinical trial, 80% (4/5) of metastatic castration-resistant prostate cancer patients with ATM truncation mutations demonstrated response to Lynparza (olaparib) treatment (Cancer Res August 1, 2015 75:CT322). | detail... |
| ATM mutant | prostate cancer | not applicable | N/A | Guideline | Risk Factor | Germline ATM mutations are associated with increased risk of developing prostate cancer (NCCN.org). | detail... |
| ATM mutant | breast cancer | not applicable | N/A | Guideline | Risk Factor | Germline ATM mutations are associated with increased risk of developing breast cancer (NCCN.org). | detail... |
| ATM mutant | chronic lymphocytic leukemia/small lymphocytic lymphoma | not applicable | N/A | Guideline | Prognostic | ATM mutations are associated with shorter time to first treatment, progression-free survival, time to next treatment, and overall survival with chemoimmunotherapy compared to wild-type ATM in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (NCCN.org). | detail... |
| ATM mutant | Advanced Solid Tumor | conflicting | Olaparib | Phase II | Actionable | In a Phase II trial (TAPUR), Lynparza (olaparib) treatment resulted in an objective response rate of 8% and a disease control rate of 25% (9/36, 1 complete response, 2 partial responses, 6 stable disease at 16+ weeks) in patients with advanced solid tumors harboring ATM mutations (Cancer Res 2022;82(12_Suppl):Abstract nr CT110; NCT02693535). | detail... |
| ATM mutant | Advanced Solid Tumor | conflicting | 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... |
| ATM 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 4 patients with metastatic breast cancer harboring only germline mutations in ATM (PMID: 33119476; NCT03344965). | 33119476 |
| ATM mutant | mantle cell lymphoma | predicted - sensitive | Ibrutinib + Venetoclax | Phase II | Actionable | In a Phase II trial (AIM), distinct molecular profiles were identified in mantle cell lymphoma patients responded to Imbruvica (ibrutinib) and Venclexta (venetoclax) combination therapy compared to those did not respond, with all patients harboring mutations in NSD2 (n=4), UBR5 (n=3), KMT2D (n=3), and 12 of 13 patients harboring mutations in ATM responded to the therapy, while SMARCA4 (n=4), CCND1 (n=2), and NOTCH1 (n=3) alterations were exclusively observed in nonresponders (PMID: 30455436; NCT02471391). | 30455436 |
| ATM mutant | pancreatic cancer | not applicable | N/A | Guideline | Risk Factor | Germline ATM mutations are associated with increased risk of developing pancreatic cancer (NCCN.org). | detail... |
| ATM mutant | ovarian cancer | not applicable | N/A | Guideline | Risk Factor | Germline ATM mutations are associated with increased risk of developing ovarian cancer (NCCN.org). | detail... |
| ATM mutant | lung non-small cell carcinoma | predicted - sensitive | M1774 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, M1774 inhibited tumor growth in a cell line xenograft model of non-small cell lung cancer harboring an ATM mutation (PMID: 38407317). | 38407317 |