NM_024408.3:c.7354C>T

NOTCH2 · NP_077719.2:p.(Gln2452Ter) · NM_024408.3

GRCh37: chr1:120457991 G>A · GRCh38: chr1:119915368 G>A

Gene: NOTCH2 Transcript: NM_024408.3

Final call

VUS

PM1 moderate PM2 moderate

Variant details

Gene

NOTCH2

Transcript

NM_024408.3

Protein

NP_077719.2:p.(Gln2452Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at moderate strength.

The truncation removes part of the PEST domain, a well-characterized functional domain responsible for NOTCH2 protein degradation, meeting PM1 at moderate strength.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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. Under PMC6185798, PVS1 requires a null variant in a gene where loss-of-function is a known disease mechanism. The truncated region (aa 2452-2472) encompasses the C-terminal portion of the PEST degradation domain. NOTCH2 PEST domain truncations are well-established as gain-of-function — the mutant protein escapes ubiquitin-mediated degradation, leading to sustained NOTCH2 signaling. This is the mechanism for Hajdu-Cheney syndrome (PMID:21378989) and has been demonstrated in lymphoma models (PMID:25314575). OncoKB classifies this variant as 'Likely Gain-of-function.' Because the predicted functional consequence is gain-of-function, not loss-of-function, PVS1 is not applicable.	pvs1_generic_framework PMID:21378989 PMID:25314575 oncokb
PS1	N/A	Nonsense variant; PS1 requires a same amino acid change as a known pathogenic missense variant, which does not apply to stop-gain variants.
PS2	Not met	No de novo observation has been reported for NM_024408.3:c.7354C>T. The variant is absent from ClinVar and no case reports document de novo inheritance.
PS3	Not met	No variant-specific functional data exists for NM_024408.3:c.7354C>T (p.Gln2452Ter). While functional studies characterize NOTCH2 PEST domain truncations broadly, available literature tested different PEST domain positions (e.g., c.7605G>A in PMID:25314575; various Hajdu-Cheney truncations in PMID:21378989) — none directly assayed the c.7354C>T variant or a systematic range that includes position 2452. Per PS3 calibration rules, domain-level inference from sparse testing falls under PM1, not PS3.	PMID:21378989 PMID:25314575
PS4	Not met	The variant is absent from ClinVar and gnomAD, so the prevalence in affected individuals versus controls cannot be assessed. No case-control data are available.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 is defined for a novel missense change at a residue where a different pathogenic missense variant has been identified. This variant is a nonsense (stop-gain), not a missense, so PS5 is not applicable.
PM1	Met	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.	PMID:21378989 PMID:25314575 oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue comparator variants were identified via ClinVar harvesting. The pm5_candidates pipeline flagged this as not applicable due to inability to confirm classic same-residue PM5 semantics. Manual review of the literature also identified no pathogenic variant at codon 2452 distinct from Q2452Ter.	pm5_candidates
PM6	Not met	No de novo report has been identified for NM_024408.3:c.7354C>T. No trio sequencing data or de novo confirmation is available.
PP1	Not met	No segregation data are available for this variant. The variant has not been reported in any family studies.
PP2	N/A	PP2 specifically applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense (stop-gain) variant, so PP2 is not applicable.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL score is unavailable for this variant. BayesDel score is 0.578, which is in the ambiguous range and does not meet a pathogenic threshold for a nonsense variant. For stop-gain variants, in silico predictors of pathogenicity are not well calibrated — the functional effect is determined by the protein truncation itself, not nucleotide conservation scores.	spliceai bayesdel
PP4	Not met	No patient phenotype data are available for this assessment. PP4 requires a variant to be identified in a patient whose phenotype or family history is highly specific for the gene/disease.
PP5	Not met	The variant is absent from ClinVar. PP5 requires a pathogenic classification from a reputable source (ClinVar expert panel with ≥3-star review status), which is not available.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1. BA1 requires an allele frequency >5% in any general population, which is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD. BS1 requires an allele frequency >0.3% (non-VCEP threshold) or greater than expected for the disorder, which is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding this variant in healthy adult individuals. The variant has not been observed in any population database.
BS3	Not met	No functional studies demonstrate a benign effect for this variant. The available functional literature on NOTCH2 PEST domain truncations supports a gain-of-function effect (increased protein stability and signaling), which is a pathogenic, not benign, mechanism.	PMID:21378989 PMID:25314575
BS4	Not met	No segregation data are available. BS4 requires lack of segregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a nonsense (truncating) variant, so BP1 is not applicable.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant has been reported. No phase data are available.
BP4	Not met	Multiple lines of computational evidence do not suggest a benign impact. SpliceAI predicts no splicing effect (max delta 0.02). BayesDel (0.578) is ambiguous. For a nonsense variant introducing a premature stop codon, computational prediction of benign impact is not persuasive.	spliceai bayesdel
BP5	Not met	No alternative molecular basis for disease has been identified in a case harboring this variant. No data are available.
BP6	Not met	The variant is absent from ClinVar. BP6 requires a benign classification from a reputable source, which is not available.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a nonsense (stop-gain) variant, not a synonymous change, so BP7 is not applicable.

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