About NOTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NOTCH1 c.1093C>T, p.(Arg365Cys)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting
Residue Arg365 is located in a statistically significant mutational hotspot as defined by cancerhotspots.org. This residue-level hotspot designation supports a functional role, although the exact variant (p.Arg365Cys) is not independently listed in the hotspot registry. PM1 is applied at supporting strength given the residue-level (rather than domain-level) hotspot evidence.
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold for absence from population databases (allele frequency <0.1% and absent in all queried populations).
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: PM1 supporting, PM2 moderate; combination = 1 moderate + 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
1 Likely pathogenic · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
21 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53025487, n = 21 times).
Cancer Hotspots
This variant lies 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 · 19 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 criterion at moderate strength for absence from population databases.
Residue Arg365 is located in a statistically significant mutational hotspot per cancerhotspots.org, meeting PM1 at supporting strength.
In silico predictions are conflicting: REVEL score 0.62 suggests a moderately damaging effect while BayesDel score 0.044 suggests a benign effect and SpliceAI predicts no splicing impact (max delta 0.00). Neither PP3 nor BP4 can be applied due to discordant predictions.
ClinVar reports conflicting classifications for this variant: Likely pathogenic (GeneDx, 1 submitter) and Uncertain significance (Labcorp Genetics, 1 submitter), both from single clinical laboratories without expert panel review. The split classification precludes application of PP5.
No variant-specific functional data are available for NM_017617.5:c.1093C>T (p.Arg365Cys). OncoKB curates this variant as Likely Oncogenic based on somatic literature, but primary publications were not available in full text for independent verification. PS3 cannot be met without experimental functional characterization.
Combined ACMG evidence: PM2 (moderate) and PM1 (supporting) are met. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), one moderate and one supporting criterion does not reach the threshold for Likely Pathogenic (requires ≥2 moderate plus ≥2 supporting, or ≥3 moderate, or 1 moderate plus ≥4 supporting). The overall classification is Uncertain Significance (VUS).
No criteria match.
Met · 2
PM1 SupportingResidue Arg365 is located in a statistically significant mutational hotspot as defined by cancerhotspots.org. This residue-level hotspot designation supports a functional role, although the exact variant (p.Arg365Cys) is not independently listed in the hotspot registry. PM1 is applied at supporting strength given the residue-level (rather than domain-level) hotspot evidence. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org identifies residue R365 as a statistically significant hotspot. The variant lies within the EGF-like repeat region of the NOTCH1 extracellular domain.
Still missing
- Exact variant not listed in cancerhotspots.org
- residue-level significance only. Domain-level functional characterization of EGF-repeat region would strengthen PM1 to moderate.
Sources
PM2 ModerateThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold for absence from population databases (allele frequency <0.1% and absent in all queried populations). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF=null)
- v4.1 (AF=null)
- and gnomAD-Canada v1.0 (AF=0.0
- AC=0
- AN=0).
Still missing
- gnomAD-Canada AN=0 indicates the variant position may not be covered in that dataset
- this does not diminish the evidence from v2.1 and v4.1.
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No known pathogenic variant with a different amino acid change at residue Arg365 was identified. PM5 candidate search returned no same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting found zero same-residue pathogenic comparator variants at Arg365.
Still missing
- No systematic literature search for same-residue pathogenic missense variants beyond ClinVar PM5 candidate harvesting.
Sources
pm5_candidatesclinvar ↗
PS2 No de novo data are available for this variant. Neither ClinVar submissions nor the literature packet contain de novo observations. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar submissions or available literature.
Still missing
- No parental testing data available.
Sources
PS3 No variant-specific functional data are available for NM_017617.5:c.1093C>T. OncoKB curates this variant as Likely Oncogenic with variant-specific literature references, but the underlying primary publications are not available in full text for independent verification. The 21 somatic occurrences in COSMIC indicate recurrence in cancer but do not constitute experimental functional characterization. No publications in the case folder directly tested p.Arg365Cys in a functional assay. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Likely Oncogenic (curated literature not independently verifiable in full text). COSMIC: 21 somatic occurrences. No primary functional assay data available for this exact variant.
Still missing
- Underlying publications from OncoKB curation not available in full text for review. Functional characterization of p.Arg365Cys (e.g.
- luciferase reporter
- NOTCH1 cleavage assay) would be needed to apply PS3.
Sources
PS4 No case-control or case series data are available establishing an association between this variant and disease. The variant is absent from gnomAD, precluding case-control comparison. ClinVar submissions do not include phenotype details beyond 'Not Provided.' Details ▾Hide ▴
Evidence considered
- Variant absent from population databases precluding case-control analysis. ClinVar submissions lack detailed phenotype data.
Still missing
- No case series or cohort data available for this variant.
Sources
PM6 No de novo data are available for this variant. PM6 requires confirmed de novo occurrence with maternity and paternity confirmation. Details ▾Hide ▴
Evidence considered
- No de novo reports in available data.
Still missing
- No parental testing or de novo confirmation data.
Sources
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No segregation analysis data.
PP3 In silico predictions are conflicting and do not support a consistent deleterious effect. REVEL score is 0.62 (moderately elevated but below strong thresholds), while BayesDel score is 0.044 (suggesting benign). SpliceAI predicts no splicing impact (max delta score 0.00). The GeneDx ClinVar submission also notes that in silico analysis is inconsistent in its predictions. Conflicting computational evidence precludes application of PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.62 (moderately damaging direction). BayesDel: 0.044 (benign direction). SpliceAI: max delta 0.00 (no splice impact). ClinVar SCV000570514: 'in silico analysis is inconsistent in its predictions.'
Sources
PP4 No detailed patient phenotype data are available for this variant. ClinVar submissions list 'Not Provided' or no condition labels, and no case reports with phenotypic descriptions were identified in the literature packet. Details ▾Hide ▴
Evidence considered
- ClinVar submissions do not include specific phenotype data. No case reports with clinical descriptions available.
Still missing
- Patient phenotype data would be needed for PP4 assessment.
Sources
PP5 ClinVar reports conflicting classifications: one submitter classifies as Likely Pathogenic (GeneDx, SCV000570514) and another as Uncertain Significance (Labcorp Genetics, SCV003459548). Both are single submitters without expert panel review. A split ClinVar classification does not meet PP5 criteria, which requires a consistent pathogenic call from a reputable source. Details ▾Hide ▴
Evidence considered
- ClinVar variation 421340: Likely pathogenic (GeneDx
- 1 submitter) and Uncertain significance (Labcorp
- 1 submitter). Conflicted classification
- no expert panel review.
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with no allele frequency data exceeding the BA1 threshold of >1% in any population. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases. No population with AF >1%.
Sources
BS1 This variant is absent from gnomAD across all queried datasets, with no allele frequency exceeding the BS1 threshold of >0.3% in any population. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases.
Sources
BS2 No data are available regarding observation of this variant in healthy adults. The variant is absent from gnomAD, precluding assessment of healthy carrier frequency. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no healthy adult carrier data available.
Still missing
- No healthy adult carrier data available.
Sources
BS3 No functional studies demonstrating no deleterious effect are available for this variant. BS3 requires well-established functional assays showing no damaging effect. No such data exist in the case folder. Details ▾Hide ▴
Evidence considered
- No functional studies showing benign effect available.
Still missing
- Functional characterization of p.Arg365Cys would be needed to assess BS3.
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. BS4 requires observation of non-segregation in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation analysis data.
BP2 No trans configuration data are available for this variant. BP2 requires observation of the variant in trans with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
- No trans observation data available.
Still missing
- No trans configuration analysis data.
BP4 In silico predictions are conflicting and do not consistently suggest a benign effect. REVEL score is 0.62 (moderately elevated), while BayesDel score is 0.044 (low/benign direction) and SpliceAI predicts no impact. The discordance among predictors precludes application of BP4, which requires multiple lines of computational evidence consistently suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.62 (damaging direction). BayesDel: 0.044 (benign direction). SpliceAI: 0.00. Conflicting predictions preclude BP4.
Sources
BP5 No alternate molecular basis for disease has been identified in the available data. BP5 requires observation of a different pathogenic variant in a case with the same phenotype. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No data on alternate molecular findings in affected individuals.
BP6 No reputable source has classified this variant as benign. ClinVar classifications are Likely pathogenic and Uncertain significance. BP6 requires a consistent benign classification from a reputable source. Details ▾Hide ▴
Evidence considered
- ClinVar variation 421340: Likely pathogenic and Uncertain significance. No benign classification.
Sources
PS5 PS5 is not applicable without family-based evidence establishing segregation or inheritance patterns. No family studies are available for this variant. Details ▾Hide ▴
Evidence considered
- PS5 requires family-based evidence not available in this case.
Still missing
- No family segregation or inheritance data.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Arg365Cys) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ClinGen SVI PVS1 generic framework (PMC6185798) is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Variant is missense substitution (c.1093C>T
- p.Arg365Cys)
- not a predicted null variant
- generic PVS1 framework does not apply.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ASkipped: no trans configuration data available for recessive assessment. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped: variant is a substitution, not an in-frame indel or stop-loss. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variants with a different pathogenic missense change were identified in ClinVar. PM5 candidate harvesting returned zero candidates at residue Arg365. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue comparator variants.
Sources
pm5_candidates
PP2 N/APP2 requires a gene-specific threshold where missense variants are a recognized mechanism and the gene has a low rate of benign missense variation. No gene-specific PP2 framework is available for NOTCH1 under generic ACMG, and NOTCH1 disease is caused by both missense and truncating variants across the gene. Details ▾Hide ▴
Evidence considered
- NOTCH1 disease mechanism involves both missense (e.g.
- p.Cys575Ser) and truncating variants. No gene-specific PP2 threshold established.
Sources
pvs1_gene_context
BP1 N/ABP1 applies when a missense variant occurs in a gene where only truncating variants are known to cause disease. NOTCH1 has both missense and truncating pathogenic variants reported in the germline literature (e.g., p.Glu756Ter, p.Cys575Ser, p.Tyr2209CysfsTer38), so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- NOTCH1 germline disease spectrum includes both missense and truncating variants (PMIDs: 41023825
- 36866832
- 36567270).
Sources
pvs1_gene_context
BP3 N/ASkipped: variant is a substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splicing impact and non-conserved nucleotide. This is a missense variant (c.1093C>T, p.Arg365Cys) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous. BP7 is restricted to synonymous variants.
Identifiers
- Gene
- NOTCH1
- Transcript
- NM_017617.5
- Coding (HGVS c.)
- NM_017617.5:c.1093C>T
- Protein (HGVS p.)
- NP_060087.3:p.(Arg365Cys)
- GRCh38
- chr9:136518597 G>A
- GRCh37
- chr9:139413049 G>A
- ClinVar
- 421340
- COSMIC
- COSV53025487
Gene diagram
Every interpreted variant in NOTCH1, mapped onto the exon structure of NM_017617.5. Select a row to find it on the plot.
NOTCH1NM_017617.5
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 NOTCH1
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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
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.620
- BayesDel
- 0.044
How the predictions were used
PP3 In silico predictions are conflicting and do not support a consistent deleterious effect. REVEL score is 0.62 (moderately elevated but below strong thresholds), while BayesDel score is 0.044 (suggesting benign). SpliceAI predicts no splicing impact (max delta score 0.00). The GeneDx ClinVar submission also notes that in silico analysis is inconsistent in its predictions. Conflicting computational evidence precludes application of PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.62 (moderately damaging direction). BayesDel: 0.044 (benign direction). SpliceAI: max delta 0.00 (no splice impact). ClinVar SCV000570514: 'in silico analysis is inconsistent in its predictions.'
Sources
BP4 In silico predictions are conflicting and do not consistently suggest a benign effect. REVEL score is 0.62 (moderately elevated), while BayesDel score is 0.044 (low/benign direction) and SpliceAI predicts no impact. The discordance among predictors precludes application of BP4, which requires multiple lines of computational evidence consistently suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.62 (damaging direction). BayesDel: 0.044 (benign direction). SpliceAI: 0.00. Conflicting predictions preclude BP4.
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splicing impact and non-conserved nucleotide. This is a missense variant (c.1093C>T, p.Arg365Cys) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous. BP7 is restricted to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.62. BayesDel score = 0.0438125.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Likely pathogenic · 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/421340/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-139413049-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-136518597-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-136518597-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_017617.5%3Ac.1093…
- OncoKB ↗www.oncokb.org/gene/NOTCH1/R365C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121930166
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 421340)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.62. BayesDel score = 0.0438125.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53025487, n = 21 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.