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Gene NOTCH1
Variant E450K
Impact List missense
Protein Effect unknown
Gene Variant Descriptions NOTCH1 E450K lies within the calcium-binding EGF-like domain 11 of the Notch1 protein (UniProt.org). E450K has been identified in the scientific literature (PMID: 24292195, PMID: 25303977, PMID: 25633867), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Feb 2021).
Associated Drug Resistance

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Transcript NM_017617.4
gDNA chr9:g.136517845C>T
cDNA c.1348G>A
Protein p.E450K
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_017617 chr9:g.136517845C>T c.1348G>A p.E450K RefSeq GRCh38/hg38
NM_017617.4 chr9:g.136517845C>T c.1348G>A p.E450K RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 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
NOTCH1 mutant chronic lymphocytic leukemia decreased response Chlorambucil + Ofatumumab Phase III Actionable In a Phase III trial (COMPLEMENT1), the addition of Arzerra (ofatumumab) to Chlorambucil treatment in patients with chronic lymphocytic leukemia was associated with increased benefit to median progression-free survival (mPFS) in patients with wild-type NOTCH1 (mPFS 23.8 mo with ofatumumab vs.13.3 mo without, HR 0.50, CI 95% 0.39-0.63, p<0.01), but did not result in significant mPFS benefit in patients with mutant NOTCH1 (17.2 vs.13.1 mo, HR 0.81, CI 95% 0.50-1.31, p=0.45) (PMID: 31919090; NCT00748189). 31919090
NOTCH1 mutant triple-receptor negative breast cancer sensitive PF-03084014 Preclinical - Pdx Actionable In a preclinical study, PF-03084014 treatment resulted in tumor regression in patient-derived xenograft models of triple receptor negative breast cancer harboring NOTCH1 mutations (PMID: 25564152). 25564152
Molecular Profile Protein Effect Treatment Approaches
NOTCH1 E450K unknown