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Gene NOTCH1
Variant I1616N
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions NOTCH1 I1616N lies within the HD-N domain of the Notch1 protein (PMID: 16738328). I1616N (reported as I1617N) results in activation of Notch1 signaling, including ligand-independent activation as indicated in a reporter assay, increased S2 and S3 proteolytic cleavage of Notch1, and altered heterodimer stability (PMID: 16738328).
Associated Drug Resistance

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Transcript NM_017617
gDNA chr9:g.136504844A>T
cDNA c.4847T>A
Protein p.I1616N
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_017617 chr9:g.136504844A>T c.4847T>A p.I1616N 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 act mut breast cancer sensitive Brontictuzumab Preclinical - Pdx Actionable In a preclinical study, Brontictuzumab (OMP-52M51) inhibited tumor growth and reduced cancer stem cells in xenograft models of tumor derived from a breast cancer patient harboring activating NOTCH1 mutations (Cancer Res 2013;73(8 Suppl):Abstract nr 3728). detail...
NOTCH1 act mut colorectal cancer sensitive PF-03084014 Preclinical - Cell culture Actionable In a preclinical study, the gamma secretase inhibitor PF-03084014 reduced Notch1 cleavage, decreased activation of Notch targets, and increased apoptosis in colorectal cancer cell lines exhibiting increased Notch activation (PMID: 23868008). 23868008
NOTCH1 act mut T-cell adult acute lymphocytic leukemia predicted - sensitive Dexamethasone + Ribociclib Preclinical - Pdx Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Adexone (dexamethasone) resulted in reduced leukemia burden and a greater survival benefit in a NOTCH1 activated T-cell acute lymphoblastic leukemia patient derived xenograft (PDX) model when compared to control or either agent alone (PMID: 28151717). 28151717
NOTCH1 act mut acute lymphoblastic leukemia sensitive Brontictuzumab Preclinical - Pdx Actionable In a preclinical study, xenograft models of patient-derived acute lymphocytic leukemia cells harboring NOTCH1 activating muatations demonstrated better response to Brontictuzumab (OMP-52M51) compared to NOTCH1 wild-type models (PMID: 23774673). 23774673
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
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 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
Molecular Profile Protein Effect Treatment Approaches
NOTCH1 I1616N gain of function Gamma secretase inhibitor NOTCH Inhibitor (Pan) NOTCH1 Antibody NOTCH1 Inhibitor