About NOTCH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NOTCH2 c.782T>G, p.(Ile261Ser)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_024408.3:c.782T>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (0 alleles across all population databases). The allele frequency (0) is below the PM2 threshold of <0.1% for a rare variant in a dominant disorder gene.
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: PM2 supporting; combination = 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.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NOTCH2 encodes a transmembrane receptor that regulates many aspects of development by affecting cell-fate determination.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
26 criteria with recorded statuses: 1 met · 19 not met · 2 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_024408.3:c.782T>G (p.Ile261Ser) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (0 alleles), meeting PM2 at supporting strength.
This variant has been reported in ClinVar (Variation ID 591665) as Uncertain significance by a single clinical testing laboratory (Labcorp Genetics, criteria provided, single submitter); no submitter has classified it as pathogenic or benign.
No published functional studies, de novo observations, case-control enrichment, or family segregation data exist for this specific variant.
In silico predictions are discordant: REVEL (0.80) supports a deleterious effect while BayesDel (0.402) does not; SpliceAI predicts no splicing impact (max delta 0.02). Neither PP3 nor BP4 can be applied.
PVS1 is not applicable as this is a missense variant outside the null-variant buckets defined by ClinGen SVI PVS1 recommendations (PMC6185798).
The only applicable criterion is PM2 (supporting); one supporting pathogenic criterion is insufficient to classify this variant above Variant of Uncertain Significance per ACMG/AMP 2015 combination rules.
No criteria match.
Met · 1
PM2 SupportingNM_024408.3:c.782T>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (0 alleles across all population databases). The allele frequency (0) is below the PM2 threshold of <0.1% for a rare variant in a dominant disorder gene. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 alleles (absent)
- gnomAD v4.1: 0 alleles (absent)
- gnomAD-Canada v1.0: 0 alleles (absent)
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No pathogenic variant with the same amino acid change (Ile261Ser) has been established in NOTCH2. PS1 requires a different nucleotide change resulting in the same amino acid change as an established pathogenic variant, which is not available. Details ▾Hide ▴
Evidence considered
- ClinVar entry 591665 classifies this variant as Uncertain significance
- not pathogenic
- No ClinVar entries for a pathogenic I261S change at this residue via a different nucleotide substitution
Sources
PS2 No de novo occurrence confirmed by both maternity and paternity testing has been reported. Exploratory search of ClinVar, Decipher, and published literature identified no de novo evidence for NM_024408.3:c.782T>G. Details ▾Hide ▴
Evidence considered
- ClinVar submissions do not report de novo origin
- Exploratory literature and database search found no de novo evidence
Still missing
- De novo screening in large-scale trio sequencing datasets (e.g.
- Decipher
- DDD) not exhaustively performed
Sources
PS3 No well-established in vitro or in vivo functional studies have been performed specifically on the I261S substitution. OncoKB identified no variant-specific functional evidence, and the exploratory literature search found no functional assays testing this variant. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence
- Exploratory search found no functional studies for I261S
Still missing
- NOTCH2 signaling reporter assays exist but have not been performed with this variant
Sources
PS4 PS4 requires statistically significant enrichment of the variant in affected individuals compared with controls. Although the variant is absent from gnomAD, no case-control studies have been conducted, and absence from population databases alone is insufficient to meet PS4. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD v2.1 and v4.1 (0 alleles)
- No case-control studies comparing prevalence in affected individuals versus controls identified
Still missing
- Case-control data comparing variant frequency in NOTCH2-associated disease cohorts versus population controls
Sources
PM5 No pathogenic missense variant at the same amino acid residue (Ile261) with a different amino acid change has been identified. The PM5 candidate collection confirmed 0 same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue candidates
- No ClinVar pathogenic entries at residue 261 with a different amino acid change
Sources
pm5_candidatesclinvar ↗
PM6 No de novo event (without confirmed maternity/paternity) has been reported. Exploratory search of ClinVar, Decipher, and literature identified no de novo observations for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar submissions do not indicate de novo origin
- Exploratory search found no de novo evidence
Still missing
- Trio-based sequencing datasets may contain unreported de novo observations
Sources
PP1 No co-segregation data with disease in multiple affected family members is available. No family studies or pedigree analyses involving this variant have been reported. Details ▾Hide ▴
Evidence considered
- Exploratory search found no family segregation data for this variant
Still missing
- No published pedigrees or segregation analyses available
PP3 In silico predictions are discordant. REVEL predicts a deleterious effect (score 0.80, above 0.5 threshold), but BayesDel does not support a deleterious effect (score 0.402, below 0.5 threshold). SpliceAI predicts no splicing impact (max delta score 0.02). Multiple lines of computational evidence do not uniformly support a deleterious effect, as required for PP3. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.80 (deleterious prediction)
- BayesDel score: 0.402 (below typical 0.5 threshold
- does not support deleterious)
- SpliceAI max delta: 0.02 (no predicted splicing impact)
Sources
PP4 No patient phenotype or family history data are available for this case. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No clinical phenotype information provided for the proband
Still missing
- Patient phenotype data not available in this case
PP5 This variant is classified as Uncertain significance in ClinVar (Variation ID 591665) by a single clinical submitter (Labcorp Genetics, criteria provided, single submitter). No reputable source has reported this variant as pathogenic. The ClinVar-submitted PMIDs (25741868 and 28492532) are methodology papers that do not mention or evaluate this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (1 submitter
- criteria provided
- single submitter)
- PMID:25741868 (ACMG 2015 guidelines) does not mention this variant
- PMID:28492532 (Sherloc) does not mention this variant
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). The BA1 threshold of >1% allele frequency is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (0 alleles)
- gnomAD v4.1: absent (0 alleles)
- Allele frequency of 0 is far below the >1% BA1 threshold
Sources
BS1 The variant is absent from all population databases (allele frequency = 0). The BS1 threshold of >0.3% allele frequency is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (0 alleles)
- gnomAD v4.1: absent (0 alleles)
- Allele frequency of 0 is below the >0.3% BS1 threshold
Sources
BS2 No observations of this variant in healthy adult controls at significant frequency have been reported. The variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD (no healthy population observations)
- No reports of observation in trans with a pathogenic variant
Sources
BS3 No well-established in vitro or in vivo functional studies have demonstrated no damaging effect for the I261S substitution. OncoKB identified no variant-specific functional evidence, and the exploratory literature search found no functional studies evaluating this variant's effect on NOTCH2 signaling. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence
- Exploratory search found no functional assays demonstrating benign effect
Still missing
- NOTCH2 signaling assays (e.g.
- luciferase reporter) have not been performed with I261S
Sources
BS4 No evidence of non-segregation with disease in affected families is available. No family studies or pedigree analyses involving this variant have been reported. Details ▾Hide ▴
Evidence considered
- Exploratory search found no family segregation or non-segregation data
Still missing
- No published pedigrees available for segregation analysis
BP2 No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder has been reported. NOTCH2-related disorders are autosomal dominant, and BP2 would require observation in trans with a known pathogenic variant without clinical consequence. Details ▾Hide ▴
Evidence considered
- No reports of this variant observed in trans with a pathogenic NOTCH2 variant
Still missing
- No trans-configuration data available for this variant
BP4 In silico predictions are discordant. While BayesDel (score 0.402) weakly suggests no impact and SpliceAI predicts no splicing effect (max delta 0.02), REVEL predicts a deleterious effect (score 0.80). Multiple lines of computational evidence do not uniformly suggest no impact on the gene product, as required for BP4. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.80 (contradicts benign prediction)
- BayesDel score: 0.402 (weakly suggests no impact)
- SpliceAI max delta: 0.02 (no predicted splicing impact)
Sources
BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. BP5 requires the variant to be found in a patient with a different established genetic cause for their phenotype. Details ▾Hide ▴
Evidence considered
- No reports of this variant co-occurring with an alternate molecular diagnosis
Still missing
- No clinical case data with alternate molecular diagnoses available
BP6 No reputable source has reported this variant as benign. The ClinVar classification is Uncertain significance (Variation ID 591665), not benign or likely benign. BP6 requires a reputable source to report the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- not benign
- Only one clinical submitter with criteria provided
Sources
Not assessed · 2 · no assessment recorded
PM1 Residue Ile261 lies within an EGF-like repeat domain (exon 5 of NOTCH2), which is critical for ligand binding and where pathogenic missense variants have been reported in Alagille syndrome. However, domain-level missense tolerance data (e.g., MetaDome, gnomAD regional missense constraint) have not been reviewed to confirm the absence of benign missense variation in this specific EGF repeat region, which is required for PM1 application. Details ▾Hide ▴
Evidence considered
- Exploratory result notes EGF repeat domain functional importance
- Residue 261 maps to an EGF-like repeat in NOTCH2
Still missing
- MetaDome domain tolerance visualization for NOTCH2 (NP_077719.2)
- gnomAD regional missense constraint metrics for the EGF repeat containing I261
PP2 While missense variants in NOTCH2 are a known disease mechanism (Alagille syndrome type 2, Hajdu-Cheney syndrome), gene-level missense constraint metrics (e.g., gnomAD missense Z-score, observed/expected ratio) have not been evaluated to confirm a low rate of benign missense variation in NOTCH2, which is required for PP2 application per ACMG/AMP 2015 guidelines. Details ▾Hide ▴
Evidence considered
- NOTCH2 missense variants are a recognized cause of Alagille syndrome and Hajdu-Cheney syndrome
- Gene-level missense constraint data not retrieved
Still missing
- gnomAD gene-level missense constraint metrics (Z-score
- oe ratio) for NOTCH2
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.782T>G, p.Ile261Ser) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per ClinGen SVI PVS1 recommendations (PMC6185798), the generic PVS1 decision tree does not apply to this variant class. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution in exon 5 (NP_077719.2:p.Ile261Ser)
- classified as variant_bucket 'other' by pvs1_variant_assessment
- apply_generic_pvs1_framework is false
- variant is not a null variant
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NOTCH2 harbors both missense (Alagille syndrome type 2, Hajdu-Cheney syndrome) and truncating pathogenic variants, so the BP1 prerequisite is not satisfied. Details ▾Hide ▴
Evidence considered
- NOTCH2 has a mixed pathogenic variant spectrum (missense and truncating)
- Known missense pathogenic variants in NOTCH2 cause Alagille syndrome and Hajdu-Cheney syndrome
Sources
pvs1_gene_context
BP7 N/AThis is a missense variant (c.782T>G, p.Ile261Ser), not a synonymous variant. BP7 applies only to synonymous (silent) variants predicted to have no impact on splicing via computational assessment. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
PS5 N/APS5 requires a different nucleotide change leading to the same amino acid change as an established pathogenic variant. No pathogenic variant resulting in Ile261Ser via a different nucleotide substitution has been reported. Details ▾Hide ▴
Evidence considered
- No established pathogenic variant producing the I261S change identified in ClinVar or literature
Sources
Identifiers
- Gene
- NOTCH2
- Transcript
- NM_024408.3
- Coding (HGVS c.)
- NM_024408.3:c.782T>G
- Protein (HGVS p.)
- NP_077719.2:p.(Ile261Ser)
- GRCh38
- chr1:119987052 A>C
- GRCh37
- chr1:120529675 A>C
- ClinVar
- 591665
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.
NOTCH2NM_024408.3
Fetching transcript structure from UCSC…
Exons
—
Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NOTCH2
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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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.800
- BayesDel
- 0.402
How the predictions were used
PP3 In silico predictions are discordant. REVEL predicts a deleterious effect (score 0.80, above 0.5 threshold), but BayesDel does not support a deleterious effect (score 0.402, below 0.5 threshold). SpliceAI predicts no splicing impact (max delta score 0.02). Multiple lines of computational evidence do not uniformly support a deleterious effect, as required for PP3. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.80 (deleterious prediction)
- BayesDel score: 0.402 (below typical 0.5 threshold
- does not support deleterious)
- SpliceAI max delta: 0.02 (no predicted splicing impact)
Sources
BP4 In silico predictions are discordant. While BayesDel (score 0.402) weakly suggests no impact and SpliceAI predicts no splicing effect (max delta 0.02), REVEL predicts a deleterious effect (score 0.80). Multiple lines of computational evidence do not uniformly suggest no impact on the gene product, as required for BP4. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.80 (contradicts benign prediction)
- BayesDel score: 0.402 (weakly suggests no impact)
- SpliceAI max delta: 0.02 (no predicted splicing impact)
Sources
BP7 N/AThis is a missense variant (c.782T>G, p.Ile261Ser), not a synonymous variant. BP7 applies only to synonymous (silent) variants predicted to have no impact on splicing via computational assessment. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.8. BayesDel score = 0.401803.
2 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
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
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 0.020
Open source ↗
ClinVar
1 Uncertain significance
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/variation/591665/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-120529675-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-119987052-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024408.3%3Ac.782T…
- OncoKB ↗www.oncokb.org/gene/NOTCH2/I261S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NOTCH2+c.782T%3EG
- 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 591665)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.8. BayesDel score = 0.401803.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NOTCH2 encodes a transmembrane receptor that regulates many aspects of development by affecting cell-fate determination.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.