NM_024408.3:c.7354C>T (p.Gln2452Ter) is a nonsense variant in the last exon of NOTCH2 that truncates the C-terminal portion of the PEST degradation domain.1 The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at moderate strength.2 The truncation removes part of the PEST domain, a well-characterized functional domain responsible for NOTCH2 protein degradation, meeting PM1 at moderate strength.3 PVS1 is not met because NOTCH2 PEST domain truncations are established as gain-of-function (Hajdu-Cheney syndrome), not loss-of-function, and the alteration predicts NMD escape.4 No variant-specific functional data, de novo reports, segregation data, or ClinVar classifications are available. Remaining criteria are not met or not applicable. Overall evidence: 2 moderate pathogenic criteria (PM1 + PM2) with no benign criteria. This combination does not reach the threshold for Likely Pathogenic under generic ACMG/AMP 2015 rules (requires 2 moderate + 2 supporting, or 3 moderate, or 1 strong + 1-2 moderate). The variant is classified as a Variant of Uncertain Significance (VUS).5
NOTCH2
Final classification
VUS
NOTCH2 c.7354C>T · p.Gln2452Ter
NOTCH2
NM_024408.3:c.7354C>T (p.Gln2452Ter) is a nonsense variant in the last exon of NOTCH2 that truncates the C-terminal portion of the PEST degradation domain.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate; combination = 2 moderate, which maps to VUS.
Classification rationale
PM1PM2
VUS
NOTCH2 c.7354C>T
PM1 + PM2
→
VUS
5
generic_acmg_combination_rules
Gene diagram
· NM_024408.3 · variants mapped to exon structure
NOTCH2
NM_024408.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
The variant p.Gln2452Ter truncates the C-terminal portion of the NOTCH2 PEST domain (approx. aa 2418-2472), a well-established functional domain responsible for ubiquitin-mediated protein degradation. PEST domain truncations in NOTCH2 are a characterized pathogenic mechanism causing Hajdu-Cheney syndrome (PMID:21378989) and have been identified in DLBCL (PMID:25314575). Truncation of this degradation domain leads to gain-of-function via increased NOTCH2 protein stability. A well-characterized functional domain in the literature satisfies PM1 for truncating variants that remove or disrupt it.
Variant truncates the PEST degradation domain (removes aa 2452-2472)PEST domain is a well-characterized functional domain controlling NOTCH2 protein turnoverPEST domain truncations are a known disease mechanism in Hajdu-Cheney syndrome and DLBCL
✓
PM2
moderate
Pathogenic
NM_024408.3:c.7354C>T is absent from gnomAD v2.1 and v4.1, meeting the PM2 threshold of allele frequency <0.1% in population databases.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (genomes/exomes)Absent from gnomAD-Canada v1.0
Assessed · not applied
Pathogenic
PVS1
NM_024408.3:c.7354C>T is a nonsense variant (p.Gln2452Ter) in the last coding exon (exon 34/34), which escapes nonsense-mediated decay.
PS2
No de novo observation has been reported for NM_024408.3:c.7354C>T.
PS3
No variant-specific functional data exists for NM_024408.3:c.7354C>T (p.Gln2452Ter).
PS4
The variant is absent from ClinVar and gnomAD, so the prevalence in affected individuals versus controls cannot be assessed.
PM5
No same-residue comparator variants were identified via ClinVar harvesting.
PM6
No de novo report has been identified for NM_024408.3:c.7354C>T.
PP1
No segregation data are available for this variant.
PP3
SpliceAI predicts no significant splice impact (max delta score = 0.02).
PP4
No patient phenotype data are available for this assessment.
PP5
The variant is absent from ClinVar.
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1.
BS1
The variant is absent from gnomAD.
BS2
No data are available regarding this variant in healthy adult individuals.
BS3
No functional studies demonstrate a benign effect for this variant.
BS4
No segregation data are available.
BP2
No observation of this variant in trans with a known pathogenic variant has been reported.
BP4
Multiple lines of computational evidence do not suggest a benign impact.
BP5
No alternative molecular basis for disease has been identified in a case harboring this variant.
BP6
The variant is absent from ClinVar.
N/A · 4
PS1 · PP2 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.577639.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
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.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.
Searched
c.7354C>TQ2452*Gln2452Ter7354
Found
Reports that heterozygous nonsense and frameshift mutations clustering in the last coding exon of NOTCH2 cause Hajdu-Cheney syndrome, an autosomal dominant skeletal disorder. The mutations are predicted to escape nonsense-mediated decay, producing truncated proteins lacking the C-terminal PEST degradation domain, consistent with a gain-of-function mechanism. NM_024408.3:c.7354C>T was not among the specific mutations reported.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
Why
Variant not specifically identified; cited for PM1 as evidence that NOTCH2 PEST domain truncations are a pathogenic gain-of-function mechanism.
All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated mRNA decay
Location Abstract
The truncate mutation of Notch2 enhances cell proliferation through activating the NF-κB signal pathway in the diffuse large B-cell lymphomas.
Searched
c.7354C>T7354Q2452Gln24527605G7605A
Found
Reports a recurrent c.7605G>A (p.Trp2435Ter) truncating mutation in the NOTCH2 PEST domain in 3 of 69 diffuse large B-cell lymphomas, demonstrating that PEST domain truncation enhances cell proliferation through NF-kappaB pathway activation. NM_024408.3:c.7354C>T (p.Gln2452Ter) was not identified in this study, though the paper establishes the functional consequence of PEST domain truncation as gain-of-function.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
Why
Variant not identified; cited for PM1 as evidence that NOTCH2 PEST domain truncations produce gain-of-function via increased protein stability and NF-kappaB activation.
The identical mutation of the three DLBCLs was at the nucleotide 7605 (G/A) in the human NOTCH2 cDNA sequence, which was in the PEST domain and converted tryptophan 2435 into a stop codon.
Location Results; Figure 1B; Table 1 · Context DLBCL tumor samples; immunohistochemistry for Notch2, P65, P50, Ki67; NF-kappaB signaling assays · full text
Sources & reference links