About NOTCH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NOTCH2 c.6205C>A, p.(Pro2069Thr)
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in gnomAD v4.1 (AF=6.2×10⁻⁷; 1/1,612,686 alleles, no homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada. The allele frequency is well below the 0.1% threshold for a dominant disorder.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.225 (below 0.5 pathogenic threshold), BayesDel is −0.234 (negative, in the benign range), and SpliceAI predicts no splicing impact (max delta 0.01). Three independent in silico tools consistently predict a benign effect.
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, BP4 supporting; combination = 1 supporting + 1 supporting benign, 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
1 / 1,612,686 alleles
gnomAD v4.1: 1 / 1,612,686 alleles. Recorded AF 6.20084e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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.
29 criteria with recorded statuses: 2 met · 21 not met · 1 not assessed · 5 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.6205C>A (p.Pro2069Thr) is a missense variant in exon 34 of NOTCH2. It is present at extremely low frequency in gnomAD v4.1 (1/1,612,686 alleles; AF=6.2×10⁻⁷) and absent from gnomAD v2.1 and gnomAD-Canada.
This variant is absent from ClinVar and has not been reported in the literature. No de novo, cosegregation, or functional data are available.
Multiple in silico tools predict a benign effect: REVEL score 0.225, BayesDel −0.234, and SpliceAI max delta 0.01.
PM2 (supporting) is met due to extreme rarity in population databases. BP4 (supporting) is met based on concordant benign in silico predictions. No other criteria are met.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is conflicting and insufficient to classify this variant as either likely pathogenic or likely benign. The variant is classified as a Variant of Uncertain Significance (VUS) per the generic ACMG/AMP 2015 framework.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in gnomAD v4.1 (AF=6.2×10⁻⁷; 1/1,612,686 alleles, no homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada. The allele frequency is well below the 0.1% threshold for a dominant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1/1
- 612
- 686 alleles (AF=6.20e-07)
- NFE subpopulation
- no homozygotes. gnomAD v2.1: absent. gnomAD-Canada: absent. Well below 0.1% PM2 threshold.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.225 (below 0.5 pathogenic threshold), BayesDel is −0.234 (negative, in the benign range), and SpliceAI predicts no splicing impact (max delta 0.01). Three independent in silico tools consistently predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.225 (benign). BayesDel: -0.234284 (benign). SpliceAI: max delta 0.01 (no splicing impact). Three concordant benign in silico predictions.
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No established pathogenic variant with the same amino acid change (Pro2069Thr or another alteration at Pro2069) has been identified in ClinVar or the literature. This variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no same-amino-acid comparator identified.
Still missing
- No ClinVar or literature data for same-residue pathogenic comparisons.
Sources
PS2 No de novo evidence is available for this variant; no parental testing data or de novo reports were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no de novo observations reported.
Still missing
- No parental or trio data available to assess de novo status.
Sources
PS3 No variant-specific functional studies were identified. In silico predictions (REVEL 0.225, BayesDel −0.234) are computational, not experimental functional data. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence. REVEL: 0.225. BayesDel: −0.234284. No experimental functional studies identified for this variant or a systematically characterized range encompassing it.
Still missing
- No laboratory-based functional characterization of p.Pro2069Thr.
Sources
PS4 No case-control or prevalence data are available to assess enrichment of this variant in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
- No case-control or cohort data available for this variant.
Still missing
- No affected-vs-control prevalence data.
PM1 Although position 2069 lies within the NOTCH2 intracellular domain near the ankyrin repeat region, the variant is not in a statistically significant mutational hotspot (cancerhotspots.org negative), and no CSPEC/VCEP domain-level specification for NOTCH2 PM1 application has been established. In the absence of domain-level guidance, PM1 cannot be applied. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant. No CSPEC/VCEP domain specification for NOTCH2.
Still missing
- No CSPEC/VCEP domain specification for NOTCH2 to guide PM1 application.
PM5 No same-residue comparator pathogenic variants were identified. Automated PM5 candidate harvesting returned no results; ClinVar contains no variants at position 2069 with an alternate pathogenic missense change. Details ▾Hide ▴
Evidence considered
- PM5 candidates: none found. ClinVar: absent for this variant and no same-residue comparators identified.
Still missing
- No same-residue pathogenic missense variants identified in ClinVar.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo evidence is available for this variant; no confirmed de novo observations were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no de novo reports available.
Still missing
- No parental testing data to confirm or exclude de novo status.
Sources
PP1 No cosegregation or family data are available for this variant. Details ▾Hide ▴
Evidence considered
- No family or cosegregation data available.
Still missing
- No family study data.
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.225 (well below the 0.5 pathogenic threshold), BayesDel is −0.234 (negative/benign range), and SpliceAI predicts no splicing impact (max delta 0.01). All available computational predictions point toward a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.225 (benign). BayesDel: -0.234284 (benign). SpliceAI: max delta 0.01 (no splicing impact).
Sources
PP4 No patient phenotype or clinical data were provided to assess whether the clinical presentation is highly specific for a NOTCH2-related disorder. Details ▾Hide ▴
Evidence considered
- No patient phenotype or clinical information available.
Still missing
- No clinical phenotype data for the proband.
PP5 This variant is absent from ClinVar; no reputable source has reported a pathogenic classification. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No expert panel or clinical laboratory classification available.
Still missing
- No prior classification from any source.
Sources
BA1 The gnomAD v4.1 allele frequency is 6.2×10⁻⁷, well below the 1% BA1 threshold for a dominant disorder. The variant is absent from gnomAD v2.1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=6.20e-07
- gnomAD v2.1 absent. Well below 1% BA1 threshold.
Sources
BS1 The gnomAD v4.1 allele frequency is 6.2×10⁻⁷, well below the 0.3% BS1 threshold. The variant is too rare to satisfy BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=6.20e-07. Well below 0.3% BS1 threshold.
Sources
BS2 A single heterozygous observation in gnomAD v4.1 (NFE male) is insufficient to establish that the variant is benign when observed in a healthy adult. NOTCH2-related disorders (Alagille syndrome, Hajdu-Cheney syndrome) may show variable expressivity and reduced penetrance; a single population observation does not exclude pathogenicity. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 heterozygous observation
- no homozygotes. Insufficient to establish benign occurrence in healthy adults for a dominant disorder with variable expressivity.
Still missing
- No phenotype data for the single gnomAD carrier.
Sources
BS3 No well-established functional studies demonstrate a neutral effect for this variant. In silico predictions (REVEL, BayesDel) are computational tools and do not constitute BS3-level experimental functional evidence. OncoKB reports no variant-specific functional data. Details ▾Hide ▴
Evidence considered
- No experimental functional studies identified. In silico scores (REVEL 0.225
- BayesDel -0.234) are computational predictions
- not BS3-qualifying functional assays.
Still missing
- No laboratory functional studies testing p.Pro2069Thr.
Sources
BS4 No segregation data are available to assess lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family or segregation data available.
Still missing
- No family segregation data.
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. NOTCH2 is associated with both Alagille syndrome (caused by missense and truncating JAG1/NOTCH2 variants) and Hajdu-Cheney syndrome (caused by truncating variants in exon 34). Since the disease spectrum includes pathogenic missense variants, BP1 does not apply. Details ▾Hide ▴
Evidence considered
- NOTCH2 disease mechanism includes pathogenic missense variants (Alagille syndrome: both missense and truncating in JAG1/NOTCH2
- Hajdu-Cheney: truncating in exon 34). BP1 is not applicable when missense variants are an established disease mechanism.
Sources
pvs1_gene_context
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans observation data available.
Still missing
- No data on observations in trans with known pathogenic variants.
BP5 No alternate molecular basis for disease has been identified in a case carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available.
Still missing
- No data on alternate molecular findings in any proband carrying this variant.
BP6 This variant is absent from ClinVar; no reputable source has reported a benign classification. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No reputable source benign classification available.
Still missing
- No prior classification from any source.
Sources
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no literature reports a pathogenic classification. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source classification available.
Still missing
- No prior classification by any reputable source.
Sources
Not assessed · 1 · no assessment recorded
PP2 Unable to assess missense constraint for NOTCH2. The HCI prior score is not available for this gene, and no gnomAD missense Z-score or constraint metrics were retrieved. Without these data, PP2 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported. No missense constraint metrics available.
Still missing
- Missing missense constraint data (Z-score
- HCI prior) for NOTCH2.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.6205C>A, p.Pro2069Thr) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution at position 2069
- variant bucket: other
- apply_generic_pvs1_framework: false.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders; NOTCH2-associated conditions (Alagille syndrome, Hajdu-Cheney syndrome) are autosomal dominant. Details ▾Hide ▴
Evidence considered
- Skipped: NOTCH2 disease mechanism is autosomal dominant.
PM4 N/APM4 applies to protein length changes (in-frame deletions/insertions, stop-loss); this is a single-nucleotide missense substitution. Details ▾Hide ▴
Evidence considered
- Skipped: this is a substitution
- not an in-frame indel or stop-loss.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is a single-nucleotide missense substitution. Details ▾Hide ▴
Evidence considered
- Skipped: this is a substitution
- not an in-frame indel in a repetitive region.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low conservation. This is a missense variant (c.6205C>A, p.Pro2069Thr), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Skipped: this is a missense variant
- not a synonymous variant.
Identifiers
- Gene
- NOTCH2
- Transcript
- NM_024408.3
- Coding (HGVS c.)
- NM_024408.3:c.6205C>A
- Protein (HGVS p.)
- NP_077719.2:p.(Pro2069Thr)
- GRCh38
- chr1:119916517 G>T
- GRCh37
- chr1:120459140 G>T
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
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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
1 / 1,612,686 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,612,686 alleles · 0 hom
| European (non-Finnish)1 / 1,178,730 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20084e-07; MAF= 0.00006%, 1/1612686 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.48371e-07; MAF= 0.00008%, 1/1178730 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.225
- BayesDel
- -0.234
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.225 (below 0.5 pathogenic threshold), BayesDel is −0.234 (negative, in the benign range), and SpliceAI predicts no splicing impact (max delta 0.01). Three independent in silico tools consistently predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.225 (benign). BayesDel: -0.234284 (benign). SpliceAI: max delta 0.01 (no splicing impact). Three concordant benign in silico predictions.
Sources
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.225 (well below the 0.5 pathogenic threshold), BayesDel is −0.234 (negative/benign range), and SpliceAI predicts no splicing impact (max delta 0.01). All available computational predictions point toward a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.225 (benign). BayesDel: -0.234284 (benign). SpliceAI: max delta 0.01 (no splicing impact).
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low conservation. This is a missense variant (c.6205C>A, p.Pro2069Thr), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Skipped: this is a missense variant
- not a synonymous variant.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.225. BayesDel score = -0.234284.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,612,686 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_024408.3%3Ac.6205C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-120459140-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-119916517-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-119916517-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024408.3%3Ac.6205…
- OncoKB ↗www.oncokb.org/gene/NOTCH2/P2069T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NOTCH2+c.6205C%3EA
- 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
This variant is present in gnomAD v4.1 (AF= 6.20084e-07; MAF= 0.00006%, 1/1612686 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.48371e-07; MAF= 0.00008%, 1/1178730 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.225. BayesDel score = -0.234284.
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.