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NOTCH2
Final classification
Likely Pathogenic
PVS1PM2
NOTCH2
c.5625del
p.Thr1876LeufsTer54
frameshift · exon 31
Gene context NCBI Gene ↗ OncoKB ↗

NOTCH2 encodes a transmembrane receptor in the Notch signaling pathway, an evolutionarily conserved cell-to-cell communication system that controls cell fate decisions during development. When engaged by ligands on adjacent cells, NOTCH2 is cleaved and its intracellular domain moves to the nucleus to regulate genes involved in cell differentiation, growth, proliferation, and survival. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, and altered NOTCH2 signaling is also associated with cancer, where it can act as either an oncogene or a tumor suppressor depending on the cellular context.

This variant

This Likely Pathogenic frameshift is predicted to eliminate NOTCH2 function through nonsense-mediated decay, the loss-of-function mechanism underlying NOTCH2-related Alagille syndrome and consistent with Hajdu-Cheney syndrome. Because NOTCH2 signaling can act as either an oncogene or a tumor suppressor depending on cellular context, the cancer relevance of this null allele would depend on the tissue in which it arises.

Transcript
NM_024408.3
HGVS · transcript:coding
NM_024408.3:c.5625del
GRCh38
chr1:119919467 TC>T
GRCh37
chr1:120462090 TC>T
Basis No ClinGen NOTCH2 framework was available, so generic ACMG/AMP 2015 rules apply: PVS1 (Very Strong) plus PM2 (Moderate) yields Likely Pathogenic. ▾
No ClinGen NOTCH2 framework was available, so generic ACMG/AMP 2015 rules apply: PVS1 (Very Strong) plus PM2 (Moderate) yields Likely Pathogenic.
Classification rationale
PVS1PM2 Likely Pathogenic
NOTCH2 c.5625del frameshift · exon 31

PVS1 (Very Strong): frameshift p.(Thr1876LeufsTer54) predicted to trigger nonsense-mediated decay in NOTCH2, which has an established loss-of-function disease mechanism. PM2 (Moderate): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Combined under ACMG/AMP 2015 rules, PVS1 (Very Strong) plus PM2 (Moderate) supports a final classification of Likely Pathogenic.

PVS1 + PM2 → Likely Pathogenic
Gene diagram · NM_024408.3 · variants mapped to exon structure
NOTCH2 NM_024408.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong Pathogenic
Met (Very Strong): frameshift p.(Thr1876LeufsTer54) predicted to trigger nonsense-mediated decay in NOTCH2, which has an established loss-of-function disease mechanism.
pvs1_variant_assessment.json classifies c.5625del as consequence_class=frameshift, variant_bucket=frameshift, and recommends applying the generic PVS1 framework at suggested_default_strength=PVS1, citing PMC6185798 (ClinGen SVI PVS1 recommendations) as the governing framework since no NOTCH2 CSPEC/VCEP PVS1 rule exists for this case.pvs1_gene_context.json confirms NOTCH2 germline loss-of-function is an established disease mechanism (pvs1_gene_gate=eligible, lof_mechanism_supported=true), based on targeted literature review of NOTCH2-related Alagille syndrome and related disorders.VariantValidator/Mutalyzer exon mapping (prefetch.json) places c.5625 within exon 31 of NOTCH2 (c.5480-5781), with the terminal coding exon being exon 34 (c.6028-*3753); the premature termination codon falls multiple exon-exon junctions upstream of the last junction, consistent with NMD-predicted decay per the >50-55nt rule in the generic PVS1 decision tree.
pvs1_generic_framework ↗PMID:16773578 ↗
✓
PM2 moderate Pathogenic
Met (Moderate): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases.
NM_024408.3:c.5625del was queried as GRCh37 1-120462090-TC-T and GRCh38 1-119919467-TC-T and was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.No NOTCH2-specific VCEP/ClinGen specification was retrieved; generic ACMG/AMP 2015 PM2 applies.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 4 not met · 13 not assessed
Pathogenic
PS2 Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available.
PS3 Not assessed: no published functional assay data for this specific variant were available.
PS4 Not assessed: no case-control or affected-versus-control data for this variant were available.
PM6 Not assessed: no de novo occurrence or parental testing results were reported.
PP1 Not assessed: no pedigree or segregation data were available.
PP3 Not met: SpliceAI max delta 0.173 is below the ~0.2 high-confidence splice-altering threshold.
PP4 Not assessed: no proband phenotype or diagnostic findings were available to evaluate phenotype specificity.
PP5 Not assessed: the exact variant has no ClinVar record with an expert-panel pathogenic assertion.
Benign
BA1 Not met: absent from all queried population databases, so the high-frequency benign threshold is not reached.
BS1 Not met: absent from population databases, so the variant's frequency cannot exceed the disorder-expected threshold.
BS2 Not assessed: no observations of the variant in healthy adults were available.
BS3 Not assessed: no functional assay data demonstrating normal function were available.
BS4 Not assessed: no pedigree or non-segregation observations were available.
BP2 Not assessed: no phase determination or observation with a second pathogenic variant was available.
BP4 Not met: SpliceAI max delta 0.173 is too high to support the ~0.1 no-splice-impact benign threshold.
BP5 Not assessed: no alternative molecular diagnosis or phenotype attribution was provided.
BP6 Not assessed: the exact variant has no ClinVar record with an expert-panel benign assertion.
N/A · 9 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 2 further PMIDs triaged but not cited — see Sources & references.
Rule & framework references · cited for criterion definitions, not variant evidence
16773578 ↗ NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway.
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 2 PMIDs not cited in assessment
15994325 ↗ Regions of Drosophila Notch that contribute to ligand binding and the modulatory influence of Fringe. ONCOKB
22006338 ↗ Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. ONCOKB