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Gene SMARCA4
Variant E821K
Impact List missense
Protein Effect loss of function
Gene Variant Descriptions SMARCA4 E821K lies within the ATP-binding helicase domain of the Smarca4 protein (UniProt.org). E821K results in cell growth similar to wild-type Smarca4 in culture, but leads to decreased nucleosomal remodeling in an vitro assay, reduced chromatin accessibility, decreased ability to activate target genes, and impaired ability to rescue cell growth of SMARCA2-deficient cells in culture (PMID: 33144586).
Associated Drug Resistance
Category Variants Paths

SMARCA4 mutant SMARCA4 inact mut SMARCA4 E821K

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Transcript NM_003072.5
gDNA chr19:g.11018979G>A
cDNA c.2461G>A
Protein p.E821K
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_003072 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027166 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451665.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_006722845.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128846.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451661.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_047439247.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_006722845 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128847 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451661.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128847.4 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001411150.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_011528198.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_006722846.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027164 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_047439250.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451658.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451659.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128844 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_011528198.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_006722846 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128846 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027165 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128846.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451662.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128849.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027167 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451663.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001387283.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451666.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_006722846.3 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027163 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_047439251.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128848.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451667.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027168 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451663.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_047439246.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_011528198 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128844.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128848.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451664.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128845.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128844.3 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_047439244.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128845.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451667.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_047439248.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128845 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128847.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128849.3 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027162 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_003072.3 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128848 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_003072.5 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_047439243.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027161 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001128849 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_017027160 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451660.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_047439249.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
XM_024451658.2 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38
NM_001374457.1 chr19:g.11018979G>A c.2461G>A p.E821K RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMARCA4 inact mut Advanced Solid Tumor no benefit Palbociclib Clinical Study Actionable In a combined analysis of 2 clinical trials (DRUP, MoST), Ibrance (palbociclib) or Kisqali (ribociclib) monotherapy had limited efficacy and resulted in no objective responses, a 15% clinical benefit rate at 16 weeks, median progression-free survival of 4 mo, and median overall survival of 5 mo in previously treated advanced solid tumor patients (n=112) with inactivating SMARCA4 mutations, CDKN2A loss, or CDK4, CDK6, CCND1, CCND2, or CCND3 amplification (PMID: 37424386; NCT02925234, ACTRN12616000931471). 37424386
SMARCA4 inact mut transitional cell carcinoma not predictive unspecified immune checkpoint inhibitor Clinical Study - Cohort Actionable In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including SMARCA4, did not correlate with improved survival in 2 separate cohorts of patients with transitional cell carcinoma treated with systemic immune checkpoint inhibitors, with adjusted HRs for overall survival of 1.44 (p=0.34, n=56) and 0.82 (p=0.559, n=93), respectively (PMID: 32321774). 32321774
SMARCA4 inact mut lung non-small cell carcinoma sensitive MK-5108 Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring an inactivating mutation in SMARCA4 demonstrated sensitivity to MK-5108 (VX-689) in culture (PMID: 28102363). 28102363
SMARCA4 inact mut head and neck squamous cell carcinoma not predictive unspecified immune checkpoint inhibitor Clinical Study - Cohort Actionable In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including SMARCA4, did not correlate with improved survival in 2 separate cohorts of patients with head and neck squamous cell carcinoma treated with systemic immune checkpoint inhibitors, with adjusted HRs for overall survival of 0.74 (p=0.631, n=31) and 0.76 (p=0.622, n=68), respectively (PMID: 32321774). 32321774
SMARCA4 inact mut lung non-small cell carcinoma sensitive Alisertib Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring an inactivating mutation in SMARCA4 demonstrated sensitivity to Alisertib (MLN8237) in culture (PMID: 28102363). 28102363
SMARCA4 inact mut colorectal adenocarcinoma unknown unspecified immune checkpoint inhibitor Clinical Study - Cohort Actionable In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including SMARCA4, correlated with improved survival in one cohort of patients with colorectal adenocarcinoma treated with systemic immune checkpoint inhibitors but not the other, with adjusted HRs for overall survival of 0.30 (p=0.03, n=35) and 0.56 (p=0.244, n=63), respectively (PMID: 32321774). 32321774
SMARCA4 inact mut gastroesophageal adenocarcinoma not predictive unspecified immune checkpoint inhibitor Clinical Study - Cohort Actionable In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including SMARCA4, did not correlate with improved survival in 2 separate cohorts of patients with gastroesophageal adenocarcinoma treated with systemic immune checkpoint inhibitors, with adjusted HRs for overall survival of 0.70 (p=0.403, n=66) and 0.46 (p=0.071, n=59), respectively (PMID: 32321774). 32321774
SMARCA4 inact mut lung non-small cell carcinoma sensitive ENMD-2076 Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring an inactivating mutation in SMARCA4 demonstrated sensitivity to ENMD-2076 in culture (PMID: 28102363). 28102363
SMARCA4 inact mut lung non-small cell carcinoma sensitive Danusertib Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring an inactivating mutation in SMARCA4 demonstrated sensitivity to Danusertib (PHA-739358) in culture (PMID: 28102363). 28102363
SMARCA4 inact mut melanoma not predictive unspecified immune checkpoint inhibitor Clinical Study - Cohort Actionable In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including SMARCA4, did not correlate with improved survival in 2 separate cohorts of patients with melanoma treated with systemic immune checkpoint inhibitors, with adjusted HRs for overall survival of 1.70 (p=0.192, n=86) and 1.02 (p=0.939, n=192), respectively (PMID: 32321774). 32321774
SMARCA4 inact mut lung non-small cell carcinoma sensitive Tozasertib Preclinical - Cell line xenograft Actionable In a preclinical study, non-small cell lung cancer cell lines harboring SMARCA4 inactivating mutations demonstrated sensitivity to Tozasertib (VX-680) in culture and in xenograft models (PMID: 28102363). 28102363
SMARCA4 mutant small-cell carcinoma of the ovary of hypercalcemic type sensitive Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) treatment of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell lines and xenografts with mutant SMARCA4 resulted in decreased cell viability and tumor volume (PMID: 29440177). 29440177
SMARCA4 mutant esophageal cancer predicted - sensitive PRT3789 Case Reports/Case Series Actionable In a Phase I trial, PRT3789 treatment was well tolerated and resulted in partial responses, tumor shrinkage, and prolonged stable disease in patients with advanced esophageal cancer (N=2) or non-small cell lung cancer (N=18) harboring SMARCA4 mutations (Ann Oncol (2024) 35 (suppl_2): S483-S484; NCT05639751). detail...
SMARCA4 mutant mantle cell lymphoma predicted - resistant 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
SMARCA4 mutant lung non-small cell carcinoma predicted - sensitive PRT3789 Phase I Actionable In a Phase I trial, PRT3789 treatment was well tolerated and resulted in partial responses, tumor shrinkage, and prolonged stable disease in patients with advanced esophageal cancer (N=2) or non-small cell lung cancer (N=18) harboring SMARCA4 mutations (Ann Oncol (2024) 35 (suppl_2): S483-S484; NCT05639751). detail...
SMARCA4 mutant lung non-small cell carcinoma predicted - sensitive Tozasertib Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring a SMARCA4 mutation demonstrated sensitivity to Tozasertib (VX-680) in culture (Cancer Res July 15 2016 (76) (14 Supplement) LB-318). detail...