About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.1149G>T, p.(Trp383Cys)
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
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, so the observed population frequency is 0 and is below the 0.1% PM2 threshold.
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
12 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62692553, n = 12 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.
28 criteria with recorded statuses: 1 met · 5 not met · 14 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
The CTNNB1 c.1149G>T (p.Trp383Cys) variant has been observed in somatic cancers 12 times in COSMIC and has also been reported in ClinVar, although ClinVar submission-level classification details were not available from the retrieved record.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, placing its observed population frequency at 0, below the 0.1% rarity threshold used for PM2.
In a published functional study of CTNNB1 armadillo repeat 5 and 6 substitutions, residue W383 was identified as recurrently mutated in cancer, and substitutions in this region were associated with reduced APC binding and increased downstream beta-catenin signaling, but direct functional testing of p.Trp383Cys was not established from the retrieved evidence.
Computational findings are concerning for a missense effect, with REVEL 0.642 and BayesDel 0.287483, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.02.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, so the observed population frequency is 0 and is below the 0.1% PM2 threshold. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2 using rarity threshold <0.1%
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
Not met · 5 · evaluated, threshold not reached
PS4 This variant has been observed in somatic cancers and has a ClinVar record, but no germline case-control enrichment or statistically increased prevalence in affected individuals was identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS4
Evidence considered
- COSMIC somatic count 12
- ClinVar record present without usable submission-level germline assertions
Still missing
- No germline prevalence study or case-control dataset was identified.
Sources
BA1 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, so the observed population frequency is 0 and is far below the 1% BA1 threshold. Details ▾Hide ▴
Rule
Generic ACMG/AMP BA1 using benign threshold >1%
Evidence considered
- Population frequency 0 across queried population datasets
Sources
BS1 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, so the observed population frequency is 0 and does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS1 using benign threshold >0.3%
Evidence considered
- Population frequency 0 across queried population datasets
Sources
BS3 Available functional literature does not show a normal or benign effect for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS3
Evidence considered
- No retrieved study demonstrated normal function for p.Trp383Cys
Still missing
- Direct benign functional data for p.Trp383Cys were not identified.
Sources
BP4 Benign computational evidence was not identified. REVEL is 0.642 and BayesDel is 0.287483, which do not support a benign missense interpretation, although SpliceAI predicts no significant splice impact with a max delta score of 0.02. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP4
Evidence considered
- REVEL 0.642
- BayesDel 0.287483
- SpliceAI max delta 0.02
Sources
Not assessed · 14 · no assessment recorded
PS1 No evidence was identified showing that this nucleotide change creates the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS1
Still missing
- A validated same-amino-acid pathogenic comparator was not identified.
PS2 No confirmed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS2
Still missing
- Parental testing and confirmed maternity/paternity data were not available.
PS3 A published study showed that CTNNB1 substitutions in armadillo repeats 5 and 6 can reduce APC binding and increase downstream signaling, but direct well-established functional testing of p.Trp383Cys was not established from the retrieved evidence. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS3
Evidence considered
- Functional literature exists for nearby armadillo repeat 5/6 substitutions
- OncoKB flagged curated variant-specific literature context
Still missing
- Direct variant-specific functional assay results for p.Trp383Cys were not confirmed.
Sources
PM1 Residue W383 lies in a recurrently mutated CTNNB1 cancer region, but the available evidence does not establish a germline disease-specific mutational hotspot or critical benign-variation-depleted region suitable for applying PM1 with confidence. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM1
Evidence considered
- Exact variant reported 12 times in COSMIC
- Published cancer recurrence at residue W383
- Cancer Hotspots artifact marked uncertain
Still missing
- No germline disease-specific hotspot framework was available for CTNNB1.
- Cancer Hotspots review was flagged as uncertain.
Sources
PM6 No assumed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM6
Still missing
- De novo occurrence information was not available.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP1
Still missing
- Family segregation data were not available.
PP2 No gene-specific evidence framework was available to support applying PP2 for this CTNNB1 missense variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP2
Still missing
- A validated CTNNB1 missense-mechanism rule for PP2 was not available.
PP3 Computational results are concerning for a missense effect, with REVEL 0.642 and BayesDel 0.287483, while SpliceAI predicts no significant splice impact with a max delta score of 0.02; however, without a gene-specific computational rule or clearly prespecified threshold for this case, these data were not used alone to apply PP3. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP3
Evidence considered
- REVEL 0.642
- BayesDel 0.287483
- SpliceAI max delta 0.02
Still missing
- No CTNNB1-specific PP3 threshold framework was available.
Sources
PP4 No phenotype data were provided to assess whether the clinical presentation is highly specific for a CTNNB1-related disorder. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP4
Still missing
- Phenotype and diagnostic specificity data were not available.
BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient to apply BS2. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS2
Still missing
- Well-phenotyped unaffected carrier data were not available.
BS4 No data were identified showing lack of segregation with disease. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS4
Still missing
- Family non-segregation data were not available.
BP1 BP1 was not applied because no gene-specific framework was available to determine whether this CTNNB1 missense change should be treated as a low-prior-probability missense mechanism. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP1
Evidence considered
- CTNNB1 loss-of-function mechanism is established
- but no missense-specific benign rule was provided
Still missing
- A validated CTNNB1-specific BP1 rule was not available.
Sources
pvs1_gene_context
BP2 No phase data with another variant were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP2
Still missing
- Compound genotype and phase information were not available.
BP5 No alternative molecular explanation was identified to support BP5. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP5
Still missing
- Independent alternate-cause data were not available.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and it does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 fallback via ClinGen SVI PVS1 recommendations
Evidence considered
- Missense substitution p.Trp383Cys
- Generic PVS1 scaffold did not identify a qualifying null-variant mechanism for this variant
Sources
PM3 N/ANo recessive context or trans observations relevant to PM3 were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM3
PM4 N/AThis is not a protein length-changing variant, so PM4 does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM4
PM5 N/AClassic same-residue PM5 logic could not be confirmed safely for this case, and no validated same-residue pathogenic comparator was identified for use. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM5
Evidence considered
- PM5 candidate review found no safe classic same-residue comparator set
Sources
pm5_candidates
PP5 N/APP5 is not applied in current ACMG/AMP interpretation practice. Details ▾Hide ▴
Rule
PP5 not used
BP3 N/AThis is not an in-frame insertion/deletion in a repetitive region, so BP3 does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP3
BP6 N/ABP6 is not applied in current ACMG/AMP interpretation practice. Details ▾Hide ▴
Rule
BP6 not used
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7
Evidence considered
- Variant is missense
- SpliceAI does not change BP7 applicability
Sources
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001904.4
- Coding (HGVS c.)
- NM_001904.4:c.1149G>T
- Protein (HGVS p.)
- NP_001895.1:p.(Trp383Cys)
- GRCh38
- chr3:41233408 G>T
- GRCh37
- chr3:41274899 G>T
- ClinVar
- 4539790
- COSMIC
- COSV62692553
Gene diagram
Every interpreted variant in CTNNB1, mapped onto the exon structure of NM_001904.4. Select a row to find it on the plot.
CTNNB1NM_001904.4
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 CTNNB1
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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
- 0.642
- BayesDel
- 0.287
How the predictions were used
BP4 Benign computational evidence was not identified. REVEL is 0.642 and BayesDel is 0.287483, which do not support a benign missense interpretation, although SpliceAI predicts no significant splice impact with a max delta score of 0.02. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP4
Evidence considered
- REVEL 0.642
- BayesDel 0.287483
- SpliceAI max delta 0.02
Sources
PP3 Computational results are concerning for a missense effect, with REVEL 0.642 and BayesDel 0.287483, while SpliceAI predicts no significant splice impact with a max delta score of 0.02; however, without a gene-specific computational rule or clearly prespecified threshold for this case, these data were not used alone to apply PP3. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP3
Evidence considered
- REVEL 0.642
- BayesDel 0.287483
- SpliceAI max delta 0.02
Still missing
- No CTNNB1-specific PP3 threshold framework was available.
Sources
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7
Evidence considered
- Variant is missense
- SpliceAI does not change BP7 applicability
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.642. BayesDel score = 0.287483.
6 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
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PMID 15579438 ↗CTNNB1 mutations and overexpression of Wnt/beta-catenin target genes in WT1-mutant Wilms' tumors.Li CM et al. · 2004No paper-specific finding is recorded.
-
PMID 31857074 ↗Oncogenic Mutations in Armadillo Repeats 5 and 6 of β-Catenin Reduce Binding to APC, Increasing Signaling and Transcription of Target Genes.Liu P et al. · 2020No paper-specific finding is recorded.
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PMID 35101336 ↗Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).Horak P et al. · 2022No paper-specific finding is recorded.
-
PMID 22918138 ↗Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.Schrijver I et al. · 2012No paper-specific finding is recorded.
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PMID 34131312 ↗Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).Shao L et al. · 2021No paper-specific finding is recorded.
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PMID 23619274 ↗American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.Cooley LD et al. · 2013No 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
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/variation/4539790/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41274899-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41233408-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-41233408-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001904.4%3Ac.1149…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/W383C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=223262158
- 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 but submission details could not be extracted. (ClinVarID = 4539790)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.642. BayesDel score = 0.287483.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62692553, n = 12 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.