About NOTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NOTCH1 c.3225G>A, p.(Trp1075Ter)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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
Nonsense variant NM_017617.5:c.3225G>A (p.Trp1075Ter) in exon 20/34 of NOTCH1 creates a premature termination codon predicted to trigger nonsense-mediated decay (NMD). Under PMC6185798, nonsense variants in genes where loss of function is an established disease mechanism are assigned PVS1 at full strength. NOTCH1 loss of function is supported for germline disease (Aortic Valve Disease 1, Adams-Oliver syndrome, congenital heart defects). The variant is absent from gnomAD and the stop codon is >50bp upstream of the last exon-exon junction, favoring NMD. The truncation removes all intracellular signaling domains including ANK repeats, TAD, and PEST.
PM2Supporting
PM2 · supporting
The variant is absent from all gnomAD population databases (v2.1 exomes, v4.1 exomes, and gnomAD-Canada v1.0 genomes), meeting the PM2 threshold of allele frequency <0.1% in population databases under generic ACMG rules.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53100468, n = 2 times).
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.
29 criteria with recorded statuses: 2 met · 12 not met · 8 not assessed · 7 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.3225G>A (p.Trp1075Ter) is a nonsense variant in NOTCH1 predicted to undergo nonsense-mediated decay, meeting PVS1 at very strong strength.
The variant is absent from all gnomAD population databases (v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.
No variant-specific functional studies, de novo observations, case-control data, or cosegregation evidence are available. ClinVar contains no entry for this variant.
Five publications identified via OncoKB discuss NOTCH1 loss-of-function in squamous cell carcinoma at the gene level, but none mention NM_017617.5:c.3225G>A specifically. COSMIC reports two somatic occurrences (COSV53100468) without functional characterization.
The met criteria are PVS1 (very_strong) and PM2 (supporting). Under generic ACMG/AMP 2015 combination rules, one very-strong criterion plus one supporting criterion does not meet the threshold for Pathogenic (requires 1 Strong, 2 Moderate, or 1 Moderate + 1 Supporting in addition to PVS1) or Likely Pathogenic (requires at least PVS1 + 1 Moderate). The variant is classified as Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PVS1 Very strongNonsense variant NM_017617.5:c.3225G>A (p.Trp1075Ter) in exon 20/34 of NOTCH1 creates a premature termination codon predicted to trigger nonsense-mediated decay (NMD). Under PMC6185798, nonsense variants in genes where loss of function is an established disease mechanism are assigned PVS1 at full strength. NOTCH1 loss of function is supported for germline disease (Aortic Valve Disease 1, Adams-Oliver syndrome, congenital heart defects). The variant is absent from gnomAD and the stop codon is >50bp upstream of the last exon-exon junction, favoring NMD. The truncation removes all intracellular signaling domains including ANK repeats, TAD, and PEST. Details ▾Hide ▴
Evidence considered
- Nonsense variant at codon 1075 in exon 20/34
- Germline LoF mechanism established for NOTCH1 (AOVD1
- Adams-Oliver syndrome)
- NMD predicted — stop codon >50bp from last exon-exon junction
- Absent from gnomAD v2.1 and v4.1
Sources
PM2 SupportingThe variant is absent from all gnomAD population databases (v2.1 exomes, v4.1 exomes, and gnomAD-Canada v1.0 genomes), meeting the PM2 threshold of allele frequency <0.1% in population databases under generic ACMG rules. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- Absent from gnomAD v4.1 (0 alleles)
- Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
Not met · 12 · evaluated, threshold not reached
PS1 No established pathogenic variant at this nucleotide position with the same predicted protein change (p.Trp1075Ter). ClinVar is absent for this variant, and no literature reports a pathogenic change at this codon. A different nucleotide substitution producing the same premature stop (e.g., c.3224G>A) would qualify, but none has been reported. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no known pathogenic comparator at this position
Still missing
- No known pathogenic same-residue comparator
Sources
PS3 No variant-specific functional assay data exist for NM_017617.5:c.3225G>A (p.Trp1075Ter). Five publications identified via OncoKB discuss NOTCH1 loss-of-function in squamous cell carcinoma at the gene level, but none directly tested this nonsense variant. No systematic range characterization (tiling screen, saturation mutagenesis) includes position 1075. COSMIC reports 2 somatic occurrences but without functional characterization. The OncoKB 'Likely Oncogenic' classification reflects somatic tumor-suppressive context, not germline functional evidence. Details ▾Hide ▴
Evidence considered
- No variant-specific functional assay identified in reviewed literature
- COSMIC somatic count (n=2) does not constitute PS3-level functional evidence
Still missing
- No functional assay data for this specific variant
Sources
PM1 The nonsense variant at position 1075 lies within the EGF repeat region of NOTCH1, which is functionally critical for ligand binding (Delta/Serrate). However, this is a nonsense variant predicted to undergo NMD, resulting in no protein expression. The PVS1 criterion already fully captures the deleterious effect of complete protein loss. Applying PM1 for a domain that is never expressed would constitute double-counting of evidence that is not independent. The residue is not a statistically significant hotspot at cancerhotspots.org. PM1 for truncating variants is more appropriately applied when the variant escapes NMD and produces a truncated protein that specifically removes a functionally characterized domain (e.g., PEST domain truncations in T-ALL). Details ▾Hide ▴
Evidence considered
- NMD-predicted nonsense
- PVS1 captures protein loss
- Not a statistically significant hotspot
- EGF repeat domain criticality is not independent evidence when NMD prevents protein expression
Sources
PP3 SpliceAI predicts no splice impact (max delta score = 0.00). BayesDel score of 0.66 is designed for missense variant deleteriousness prediction and is not informative for a nonsense change. REVEL and HCI prior scores are unavailable. The deleterious effect of this nonsense variant is already captured by PVS1 (which incorporates the anticipated null effect) and should not be independently credited through PP3 to avoid double-counting. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice alteration
- BayesDel 0.66 not calibrated for nonsense variants
- PVS1 already captures the deleterious effect of protein truncation/NMD
Sources
spliceai ↗bayesdel
PP5 The variant is absent from ClinVar. No expert panel or reputable germline source has classified this variant. PP5 requires a reputable source asserting pathogenicity, which is not available. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no expert panel or submitter classification available
Still missing
- No ClinVar entry
- no expert panel classification
Sources
BA1 The variant is absent from gnomAD v2.1 and v4.1. An allele frequency >1% (BA1 threshold) is not observed. Details ▾Hide ▴
Evidence considered
- gnomAD allele frequency = 0.0 — does not meet BA1 threshold (>1%)
Sources
BS1 The variant is absent from gnomAD. An allele frequency >0.3% (BS1 threshold for non-VCEP) is not observed. Details ▾Hide ▴
Evidence considered
- gnomAD allele frequency = 0.0 — does not meet BS1 threshold (>0.3%)
Sources
BS2 The variant is absent from gnomAD. No observation in healthy adults at significant frequency is available. This variant has not been observed in any population database. Details ▾Hide ▴
Evidence considered
- Zero observations across all gnomAD populations
Sources
BS3 No well-established functional studies demonstrate a neutral effect for this variant. The available literature on NOTCH1 loss-of-function mutations (PMID:22006338, PMID:21798897) indicates that truncating NOTCH1 variants abrogate receptor signaling in squamous cell carcinomas, consistent with a tumor-suppressive loss-of-function mechanism. This evidence is directionally consistent with pathogenicity, not benign effect. Details ▾Hide ▴
Evidence considered
- Published literature demonstrates NOTCH1 truncations result in loss of signaling function
- No functional study showing neutral effect exists
Still missing
- No functional study directly testing this variant for neutral effect
Sources
BP4 SpliceAI predicts no splicing impact (max delta = 0.00), indicating no cryptic splice site creation or disruption. However, this variant's primary mechanism is protein truncation via a premature stop codon/NMD, not splice alteration. The SpliceAI benign prediction does not negate the established deleterious mechanism of nonsense-mediated decay, which is already addressed by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no cryptic splice impact
- Benign splice prediction does not negate the nonsense/NMD mechanism
Sources
BP6 The variant is absent from ClinVar. No reputable source reports this variant as benign. Details ▾Hide ▴
PS5 No reputable germline source reports this variant as pathogenic. The variant is absent from ClinVar. OncoKB classifies it as 'Likely Oncogenic' in a somatic context, which does not satisfy PS5 requirements for a germline classification. COSMIC presence (2 somatic occurrences) does not constitute a reputable germline pathogenicity assertion. Details ▾Hide ▴
Not assessed · 8 · no assessment recorded
PS2 No de novo testing data (maternity and paternity confirmation) provided for this case. Details ▾Hide ▴
Still missing
- De novo status not tested
PS4 No case-control comparison data or disease-specific prevalence statistics provided for this variant in the phenotype associated with NOTCH1 germline disease. Details ▾Hide ▴
Still missing
- No case/control or enrichment data available
PM6 No de novo observation data (with or without confirmation of paternity/maternity) provided for this variant. Details ▾Hide ▴
Still missing
- De novo occurrence not evaluated
PP1 No family cosegregation data provided for this variant. Details ▾Hide ▴
Still missing
- No cosegregation analysis performed
PP4 No patient phenotype data provided to evaluate whether the clinical presentation is highly specific for NOTCH1-related disease (AOVD1, Adams-Oliver syndrome, congenital heart defects). Details ▾Hide ▴
Still missing
- No phenotype data available for specificity assessment
BS4 No family segregation data available to evaluate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No family data for segregation analysis
BP2 No data on observation in trans with a known pathogenic variant in NOTCH1 (autosomal dominant AOVD1/Adams-Oliver syndrome). Details ▾Hide ▴
Still missing
- No trans-phase data for this dominant disorder
BP5 No data on an alternate molecular basis for disease in an individual carrying this variant. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data available
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 applies to recessive disorders with a pathogenic variant in trans. NOTCH1-related disorders (AOVD1, Adams-Oliver syndrome) are autosomal dominant. No recessive disease association is established. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants altering protein length. This is a single-nucleotide nonsense substitution resulting in protein truncation via premature stop codon, classified under PVS1. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to missense variants at an amino acid residue where a different pathogenic missense change has been observed. This variant is a nonsense substitution (p.Trp1075Ter), not a missense change. No same-residue missense comparator candidates were identified. Details ▾Hide ▴
Evidence considered
- Nonsense variant — PM5 semantics require a missense change at a residue with a known pathogenic missense alterant
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense variant, not a missense change. Details ▾Hide ▴
Evidence considered
- Nonsense variant — PP2 criterion is missense-specific
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are the established disease mechanism. This variant is itself a truncating (nonsense) variant. Details ▾Hide ▴
Evidence considered
- Nonsense/truncating variant — BP1 is missense-specific
BP3 N/ABP3 applies to in-frame indels in repetitive regions without known function. This is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a nonsense substitution (c.3225G>A, p.Trp1075Ter), not a synonymous change. Details ▾Hide ▴
Evidence considered
- Nonsense variant — BP7 requires a synonymous change
Identifiers
- Gene
- NOTCH1
- Transcript
- NM_017617.5
- Coding (HGVS c.)
- NM_017617.5:c.3225G>A
- Protein (HGVS p.)
- NP_060087.3:p.(Trp1075Ter)
- GRCh38
- chr9:136508332 C>T
- GRCh37
- chr9:139402784 C>T
- COSMIC
- COSV53100468
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.660
How the predictions were used
PP3 SpliceAI predicts no splice impact (max delta score = 0.00). BayesDel score of 0.66 is designed for missense variant deleteriousness prediction and is not informative for a nonsense change. REVEL and HCI prior scores are unavailable. The deleterious effect of this nonsense variant is already captured by PVS1 (which incorporates the anticipated null effect) and should not be independently credited through PP3 to avoid double-counting. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice alteration
- BayesDel 0.66 not calibrated for nonsense variants
- PVS1 already captures the deleterious effect of protein truncation/NMD
Sources
spliceai ↗bayesdel
BP4 SpliceAI predicts no splicing impact (max delta = 0.00), indicating no cryptic splice site creation or disruption. However, this variant's primary mechanism is protein truncation via a premature stop codon/NMD, not splice alteration. The SpliceAI benign prediction does not negate the established deleterious mechanism of nonsense-mediated decay, which is already addressed by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no cryptic splice impact
- Benign splice prediction does not negate the nonsense/NMD mechanism
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a nonsense substitution (c.3225G>A, p.Trp1075Ter), not a synonymous change. Details ▾Hide ▴
Evidence considered
- Nonsense variant — BP7 requires a synonymous change
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). 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
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PMID 1657403 ↗Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor.Characterizes the role of Drosophila Notch EGF repeats 11 and 12 in mediating interactions with Delta and Serrate ligands using deletion mutagenesis and cell aggregation assays in S2 cells. Demonstrates that EGF repeats 11-12 are both necessary and sufficient for ligand binding.Does not name this variant
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PMID 21798893 ↗The mutational landscape of head and neck squamous cell carcinoma.Whole-exome sequencing of 74 HNSCC tumor-normal pairs identifies recurrent mutations in NOTCH1 among other cancer genes. Reports NOTCH1 as significantly mutated in HNSCC with predominantly inactivating mutations, supporting a tumor-suppressive role in this cancer type.Does not name this variant
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PMID 21798897 ↗Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.Whole-exome sequencing of 32 HNSCC tumors identifies inactivating mutations in NOTCH1, including nonsense and frameshift mutations. Reports that 15% of tumors harbor NOTCH1 mutations, predominantly truncating, consistent with a tumor-suppressor role in head and neck cancer.Does not name this variant
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PMID 22006338 ↗Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.Identifies NOTCH1 or NOTCH2 loss-of-function mutations in approximately 75% of cutaneous SCCs and a lesser fraction of lung SCCs. Functionally characterizes specific missense mutations (D469G in EGF repeat 12, R1594Q in heterodimerization domain, P1770S in RAM domain) showing they abrogate Notch signaling in cell-based reporter assays. Describes truncating mutations (nonsense/frameshift) as inactivating events, noting that all nonsense mutations lie within or N-terminal of the ankyrin repeats required for all known Notch functions. Provides domain-level functional evidence for EGF repeats, heterodimerization domain, and RAM domain in Notch signaling.Does not name this variant
Quoted passage
All of the nonsense mutations lie within or N-terminal of the Notch ankyrin repeats, which are required for all known Notch functions.
Table 1 (mutation list); Figure 1 (domain distribution); Figures 2-3 (functional assays)
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PMID 24651013 ↗From fly wings to targeted cancer therapies: a centennial for notch signaling.Comprehensive review of Notch signaling in cancer covering both oncogenic and tumor-suppressive roles across hematopoietic malignancies and solid tumors. Describes the domain architecture of NOTCH1 (EGF repeats, LNR, HD, TM, RAM, ANK, TAD, PEST) and catalogs mutation patterns in different cancer types. Notes that squamous cell carcinoma NOTCH1 mutations are predominantly inactivating and cluster in the EGF repeat region, contrasting with gain-of-function mutations in the PEST and HD domains seen in T-ALL and CLL.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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.3225G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-139402784-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-136508332-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-136508332-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_017617.5%3Ac.3225…
- OncoKB ↗www.oncokb.org/gene/NOTCH1/W1075*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121951194
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). 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 previously been reported in somatic cancers (COSMIC; COSV53100468, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.