NOTCH2 c.7354C>T, p.(Gln2452Ter)

26 criteria with recorded statuses: 2 met · 19 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/ANonsense variant; PS1 requires a same amino acid change as a known pathogenic missense variant, which does not apply to stop-gain variants. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene

NOTCH2

Transcript

NM_024408.3

Coding (HGVS c.)

NM_024408.3:c.7354C>T

Protein (HGVS p.)

NP_077719.2:p.(Gln2452Ter)

GRCh38

chr1:119915368 G>A

GRCh37

chr1:120457991 G>A

Gene diagram

Every interpreted variant in NOTCH2, mapped onto the exon structure of NM_024408.3. Select a row to find it on the plot.

Statements

SpliceAI and Pangolin

Other predictors

REVEL

Not available

BayesDel

0.578

How the predictions were used

PP3 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. Details ▾Hide ▴

Evidence considered

• SpliceAI max delta = 0.02 (no predicted splicing impact)
• BayesDel = 0.578 (ambiguous range)
• REVEL not available

Sources

spliceai ↗bayesdel

BP4 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. Details ▾Hide ▴

Evidence considered

• SpliceAI max delta = 0.02 (no splice impact)
• BayesDel = 0.578 (ambiguous
• not clearly benign)

Sources

spliceai ↗bayesdel

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Statement

2 paper records listed. 2 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

• Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.

  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.

  → PM1 Does not name this variant
  PMID 21378989 ↗
  Source detail

  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.

  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.

  → PM1 Does not name this variant
  PMID 25314575 ↗
  Source detail

  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

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

• ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_024408.3%3Ac.7354C%3ET
• gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-120457991-G-A?dataset=gnomad_r2_1
• gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-119915368-G-A?dataset=gn…
• gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-119915368-G-A
• SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024408.3%3Ac.7354…
• OncoKB ↗www.oncokb.org/gene/NOTCH2/Q2452*
• COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NOTCH2+c.7354C%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.