Gene Variant Detail

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Gene NOTCH1
Variant S2467fs
Impact List frameshift
Protein Effect unknown
Gene Variant Descriptions NOTCH1 S2467fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2467 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). S2467fs does not result in statistically significant increase of Notch1 signaling in a reporter assay (PMID: 27870570), but has not been fully characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Mar 2020).
Associated Drug Resistance

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Transcript NM_017617
gDNA chr9:g.136496344_136496345insTT
cDNA c.7394_7395insAA
Protein p.S2467fs*11
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_017617 chr9:g.136496344_136496345insTT c.7394_7395insAA p.S2467fs*11 RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 L1600Q NOTCH1 S2467fs adenoid cystic carcinoma predicted - sensitive Brontictuzumab Case Reports/Case Series Actionable In a clinical case study, a patient with metastatic adenoid cystic carcinoma harboring co-occurring NOTCH1 L1600Q and S2467fs achieved a partial response after 2 doses of Brontictuzumab (OMP-52M51), however, his disease progressed shortly after treatment discontinuation (PMID: 27870570). 27870570
FBXW7 W606* NOTCH1 L1600Q NOTCH1 V1721G NOTCH1 S2467fs adenoid cystic carcinoma no benefit Sunitinib Case Reports/Case Series Actionable In a clinical case study, Sutent (sunitinib) treatment resulted in rapid disease progression in a patient with metastatic adenoid cystic carcinoma harboring co-occurring NOTCH1 L1600Q and S2467fs, and acquired FBXW7 W606* and NOTCH1 V1721G (PMID: 27870570). 27870570
FBXW7 W606* NOTCH1 L1600Q NOTCH1 V1721G NOTCH1 S2467fs adenoid cystic carcinoma predicted - resistant Brontictuzumab Case Reports/Case Series Actionable In a clinical case study, FBXW7 W606* and NOTCH1 V1721G were identified at disease progression in a patient with metastatic adenoid cystic carcinoma harboring co-occurring NOTCH1 L1600Q and S2467fs who was treated with Brontictuzumab (OMP-52M51) (PMID: 27870570). 27870570
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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
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