About NOTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NOTCH1 c.5353G>T, p.(Glu1785Ter)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_017617.5:c.5353G>T is a nonsense variant (NP_060087.3:p.Glu1785Ter) in exon 28 of 34, predicted to trigger nonsense-mediated decay (PTC >55nt upstream of the final exon-exon junction). NOTCH1 has an established loss-of-function disease mechanism (autosomal dominant Adams-Oliver syndrome and congenital heart defects), with ClinGen haploinsufficiency score 3 (sufficient evidence). Under PMC6185798, a nonsense variant in a gene with established LoF disease mechanism qualifies for PVS1 at full strength. The variant lies upstream of the PEST domain (residues ~2400-2555), where population-tolerant truncations have been observed; this is not a region of concern for PVS1 downgrade.
PM2Moderate
PM2 · moderate
NM_017617.5:c.5353G>T is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,612,390 alleles). Under generic ACMG/AMP rules, PM2 is met when a variant is absent from large population databases or present at an allele frequency <0.1%.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
0 / 1,612,390 alleles
gnomAD v4.1: 0 / 1,612,390 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_017617.5:c.5353G>T (NP_060087.3:p.Glu1785Ter) is a nonsense variant in exon 28 of 34 in NOTCH1, predicted to result in premature termination and nonsense-mediated decay, triggering loss of function. NOTCH1 loss of function is an established disease mechanism for autosomal dominant Adams-Oliver syndrome and congenital heart defects, with ClinGen haploinsufficiency score 3 (PVS1).
The variant is absent from gnomAD v2.1 and v4.1 (0/1,612,390 alleles) and from all population subpopulations, meeting PM2.
No case reports, segregation data, de novo observations, or functional studies specific to this variant were identified. The variant is absent from ClinVar. Five OncoKB-linked publications discuss NOTCH1 loss-of-function in somatic squamous cell carcinomas but none mention this specific variant.
Under ACMG/AMP 2015 combination rules, one very strong (PVS1) and one moderate (PM2) criterion yields a classification of Pathogenic.
No criteria match.
Met · 2
PVS1 Very strongNM_017617.5:c.5353G>T is a nonsense variant (NP_060087.3:p.Glu1785Ter) in exon 28 of 34, predicted to trigger nonsense-mediated decay (PTC >55nt upstream of the final exon-exon junction). NOTCH1 has an established loss-of-function disease mechanism (autosomal dominant Adams-Oliver syndrome and congenital heart defects), with ClinGen haploinsufficiency score 3 (sufficient evidence). Under PMC6185798, a nonsense variant in a gene with established LoF disease mechanism qualifies for PVS1 at full strength. The variant lies upstream of the PEST domain (residues ~2400-2555), where population-tolerant truncations have been observed; this is not a region of concern for PVS1 downgrade. Details ▾Hide ▴
Evidence considered
- Nonsense variant (p.Glu1785Ter
- p.E1785*) in exon 28/34
- NMD predicted (distance from PTC to last exon-exon junction: 2315 nt)
- NOTCH1 LoF is an established germline disease mechanism (Adams-Oliver syndrome
- aortic valve disease)
- ClinGen Dosage Sensitivity score 3 for NOTCH1 haploinsufficiency
- Variant upstream of the PEST domain
- no concern for population-tolerant C-terminal truncation
Sources
PM2 ModerateNM_017617.5:c.5353G>T is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,612,390 alleles). Under generic ACMG/AMP rules, PM2 is met when a variant is absent from large population databases or present at an allele frequency <0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 0/1
- 612
- 390 alleles (AF=0.0)
- All subpopulations: AF=0.0
Sources
Not met · 18 · evaluated, threshold not reached
PS1 PS1 applies when the same amino acid change has been established as pathogenic via a different nucleotide substitution. No prior pathogenic variant creating a stop at codon 1785 (E1785*) was identified in ClinVar or the literature. Details ▾Hide ▴
No further detail was recorded.
PS2 No de novo observation of NM_017617.5:c.5353G>T with confirmed parentage has been reported. While de novo NOTCH1 variants are documented in Adams-Oliver syndrome (Stittrich et al. 2014), this specific variant has not been observed as de novo. Details ▾Hide ▴
Still missing
- No published de novo report for this exact variant with confirmed parentage
PS3 No well-established in vitro or in vivo functional studies have been performed specifically on NM_017617.5:c.5353G>T (p.E1785*) in a germline context. OncoKB annotation of Likely Oncogenic reflects somatic cancer context, not germline functional validation; this does not substitute for PS3-level functional evidence under ACMG/AMP. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Oncogenic (somatic context
- not germline PS3)
Still missing
- No variant-specific functional assays (e.g.
- luciferase reporter
- NMD confirmation
- animal model)
Sources
165740321798893217988972200633824651013
PS4 No case-control studies, cohort reports, or individual case reports have identified NM_017617.5:c.5353G>T in affected individuals. The variant is absent from ClinVar, and no published clinical observations were found. Details ▾Hide ▴
Still missing
- No reported probands with this variant
- No case-control data comparing affected vs. population controls
PM1 Residue E1785 does not lie within a statistically significant mutational hotspot per Cancer Hotspots. No CSPEC/VCEP-defined critical functional domain encompasses this residue for NOTCH1. Codon 1785 falls in the intracellular domain but is not within a domain with established clustering of pathogenic germline missense variants. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- No VCEP-defined critical domain includes this residue
PM6 No observation of NM_017617.5:c.5353G>T as a de novo event (with or without confirmed parentage) has been reported. Details ▾Hide ▴
Still missing
- No de novo case report for this exact variant
PP1 No published segregation data available for NM_017617.5:c.5353G>T in families with multiple affected members. Details ▾Hide ▴
Still missing
- No familial segregation data
PP4 No patient phenotype or family history data are available for NM_017617.5:c.5353G>T. PP4 requires the variant to be identified in a patient with a phenotype highly specific for the gene/disease. Details ▾Hide ▴
Still missing
- No proband phenotype data available
PP5 No reputable source (e.g., clinical diagnostic laboratory, ClinVar) has reported NM_017617.5:c.5353G>T as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
No further detail was recorded.
BA1 NM_017617.5:c.5353G>T has an allele frequency of 0.0 in gnomAD v4.1, well below the BA1 threshold of >1% (or >5%). Details ▾Hide ▴
BS1 NM_017617.5:c.5353G>T has an allele frequency of 0.0, well below the BS1 threshold of >0.3% under generic ACMG rules. Details ▾Hide ▴
BS2 BS2 requires observation in a healthy adult for a fully penetrant dominant disorder. NM_017617.5:c.5353G>T has not been observed in any population database (0 alleles in gnomAD), and no healthy adult carriers have been reported. Details ▾Hide ▴
No further detail was recorded.
BS3 No well-established functional studies demonstrate a neutral or benign effect for NM_017617.5:c.5353G>T. OncoKB annotation indicates a likely loss-of-function effect, which is consistent with a damaging impact rather than a benign one. The somatic cancer literature (HNSCC, SCC) supports NOTCH1 as a tumor suppressor where truncating mutations are pathogenic in a somatic context. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Loss-of-function (somatic context)
- Five papers from OncoKB literature all discuss NOTCH1 LoF in squamous cell carcinomas
- none demonstrate a benign functional effect
Still missing
- No variant-specific benign functional data
Sources
165740321798893217988972200633824651013
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. The variant is absent from population databases, so no unaffected carrier data exists. Details ▾Hide ▴
Still missing
- No familial segregation or unaffected-carrier data
BP2 No observation of NM_017617.5:c.5353G>T in trans with a known pathogenic NOTCH1 variant in a healthy individual. NOTCH1 is an autosomal dominant gene; BP2 would require observation in trans with a pathogenic variant without clinical manifestations. Details ▾Hide ▴
No further detail was recorded.
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such observation has been reported for NM_017617.5:c.5353G>T. Details ▾Hide ▴
No further detail was recorded.
BP6 No reputable source has reported NM_017617.5:c.5353G>T as benign. The variant is absent from ClinVar. Details ▾Hide ▴
No further detail was recorded.
PS5 No reputable source (ClinVar, clinical laboratory, or published report) has classified NM_017617.5:c.5353G>T as pathogenic. The variant is absent from ClinVar. OncoKB Likely Oncogenic annotation is a somatic cancer resource and does not qualify as a germline diagnostic classification source. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/APM5 applies to missense variants at the same codon where a different pathogenic missense change is established. NM_017617.5:c.5353G>T is a nonsense variant. No PM5 candidate comparators were identified. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. NM_017617.5:c.5353G>T is a nonsense variant, not a missense change. Details ▾Hide ▴
No further detail was recorded.
PP3 N/APP3 applies to missense variants where multiple lines of computational evidence support a deleterious effect. NM_017617.5:c.5353G>T is a nonsense variant creating a premature termination codon; the deleterious nature of loss-of-function is already captured by PVS1. Computational predictors are not informative for this variant type. BayesDel score 0.66 is noted but not used to apply PP3 to a nonsense variant. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splice effect)
- BayesDel: 0.66 (not used for nonsense variant)
- REVEL: not found
- HCI prior: not applicable
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_017617.5:c.5353G>T is itself a truncating (nonsense) variant. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 applies to missense variants with multiple lines of computational evidence suggesting no impact. NM_017617.5:c.5353G>T is a nonsense variant creating a premature termination codon; the functional consequence (loss of function) is unequivocal regardless of computational predictions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_017617.5:c.5353G>T is a nonsense (stop-gain) variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NOTCH1
- Transcript
- NM_017617.5
- Coding (HGVS c.)
- NM_017617.5:c.5353G>T
- Protein (HGVS p.)
- NP_060087.3:p.(Glu1785Ter)
- GRCh38
- chr9:136502303 C>A
- GRCh37
- chr9:139396755 C>A
Gene diagram
Every interpreted variant in NOTCH1, mapped onto the exon structure of NM_017617.5. Select a row to find it on the plot.
NOTCH1NM_017617.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NOTCH1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
0 / 1,612,390 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,612,390 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1612390 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75052 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.660
How the predictions were used
PP3 N/APP3 applies to missense variants where multiple lines of computational evidence support a deleterious effect. NM_017617.5:c.5353G>T is a nonsense variant creating a premature termination codon; the deleterious nature of loss-of-function is already captured by PVS1. Computational predictors are not informative for this variant type. BayesDel score 0.66 is noted but not used to apply PP3 to a nonsense variant. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splice effect)
- BayesDel: 0.66 (not used for nonsense variant)
- REVEL: not found
- HCI prior: not applicable
BP4 N/ABP4 applies to missense variants with multiple lines of computational evidence suggesting no impact. NM_017617.5:c.5353G>T is a nonsense variant creating a premature termination codon; the functional consequence (loss of function) is unequivocal regardless of computational predictions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_017617.5:c.5353G>T is a nonsense (stop-gain) variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 1657403 ↗Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor.No paper-specific finding is recorded.
-
PMID 21798893 ↗The mutational landscape of head and neck squamous cell carcinoma.No paper-specific finding is recorded.
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PMID 21798897 ↗Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.No paper-specific finding is recorded.
-
PMID 22006338 ↗Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.No paper-specific finding is recorded.
-
PMID 24651013 ↗From fly wings to targeted cancer therapies: a centennial for notch signaling.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,612,390 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_017617.5%3Ac.5353G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-139396755-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-136502303-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_017617.5%3Ac.5353…
- OncoKB ↗www.oncokb.org/gene/NOTCH1/E1785*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NOTCH1+c.5353G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1612390 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75052 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.