Gene Variant Detail

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Gene ATM
Variant K468fs
Impact List frameshift
Protein Effect loss of function - predicted
Gene Variant Descriptions ATM K468fs results in a change in the amino acid sequence of the Atm protein beginning at 468 of 3056, likely resulting in premature truncation of the functional protein (UniProt.org). K468fs has not been characterized, however, due to the effects of other truncation mutations downstream of K468 (PMID: 16603769), is predicted to lead to a loss of Atm protein function.
Associated Drug Resistance
Category Variants Paths

ATM mutant ATM inact mut ATM K468fs

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Transcript NM_000051.4
gDNA chr11:g.(108250866_108250867)
cDNA c.(1402_1401)
Protein p.K468fs
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
XM_005271562.5 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
NM_000051 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
XM_017017789.2 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
NM_001351834.1 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_047426976.1 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_011542840.3 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_011542840 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
XM_011542843.2 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_005271561 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
XM_005271562.6 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_006718843.5 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_017017792.2 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_017017791 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
XM_005271562 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
XM_006718843 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
XM_047426975.1 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_011542843 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
XM_006718843.4 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_017017792 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
NM_000051.4 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_017017790 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38
XM_017017790.2 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_011542843.3 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
NM_000051.3 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
NM_001351834.2 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_047426981.1 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_017017790.3 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_017017791.1 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_011542840.4 chr11:g.(108250866_108250867) c.(1402_1401) p.K468fs RefSeq GRCh38/hg38
XM_017017789 chr11:g.108250867_108250868delAA c.1402_1403delAA p.K468fs*18 RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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 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 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 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 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 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 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 advanced solid tumor patients with inactivating mutations in DNA damage repair genes, including ATM with a CBR of 44.1% (15/34) and CBR was 54% (7/13) with biallelic vs 11% (1/9) with monoallelic ATM inactivation, and CBR of 75% and mPFS of 35 weeks in 20 ovarian cancer patients (PMID: 37277454; NCT04497116). 37277454
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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
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 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 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...