About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.98C>A, p.(Ser33Tyr)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
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: 4
Benign evidence criteria: 1
Pathogenic criteria applied · 4
PS3Strong
PS3 · strong
The exact variant p.Ser33Tyr has been directly tested in functional assays in at least two independent publications. Groen et al. (2008, PMID:18757411) identified S33Y in a primary T-LBL/ALL and demonstrated that S33Y h-catenin transfection into T-LBL/ALL cell lines enhanced TCF-mediated transcription and promoted cell growth. Pilati et al. (2014, PMID:24735922) tested S33Y in a TOP-FLASH luciferase reporter assay in Huh7 cells, confirming strong activation of beta-catenin transcriptional activity. Both studies demonstrate unequivocal gain-of-function: the variant disrupts the GSK-3beta phosphorylation site at serine 33, preventing ubiquitin-mediated degradation and causing constitutive beta-catenin stabilization and transcriptional activation.
PM1Moderate
PM1 · moderate
The variant is located at codon 33 (serine 33), one of the four critical GSK-3beta phosphorylation sites (S33, S37, T41, S45) within the N-terminal degradation domain of beta-catenin (amino acids 29-49). This domain is essential for ubiquitin-mediated degradation of beta-catenin. Mutations at these residues are well-established to cause beta-catenin stabilization and constitutive WNT pathway activation. Cancer Hotspots identifies this residue as statistically significant. The N-terminal domain is a well-characterized functional domain critical to beta-catenin regulation.
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 across all populations. The complete absence from large population databases supports pathogenicity.
PM5Moderate
PM5 · moderate
Multiple different missense changes at codon 33 have been reported as pathogenic in the literature and ClinVar. Specifically, S33F (TCT→TTT) and S33C (TCT→TGT) are established pathogenic variants at the same residue. S33F was reported in pilomatricomas (PMID:10192393, 2 cases), medulloblastomas (PMID:16685513, 3 cases; PMID:16258095, codon 33 TCT→TTT; SER→PHE), and T-cell lymphoma (PMID:18757411, 1 case). S33C was reported in medulloblastomas (PMID:16685513, 2 cases). These same-residue comparator variants with different amino acid changes satisfy PM5 under generic ACMG/AMP.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest a lack of deleterious effect. REVEL score is 0.495, below the typical 0.5 pathogenic threshold. BayesDel score is 0.0085, a very low value not consistent with damaging effect. SpliceAI max delta score is 0.00, indicating no predicted impact on splicing. While REVEL is borderline, the consensus of three independent in silico predictors leans toward a benign interpretation.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 moderate, PM5 moderate, BP4 supporting benign; combination = 1 strong + 3 moderate + 1 supporting benign, which maps to Pathogenic.
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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: no assertion criteria provided.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
103 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62688644, n = 103 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.
26 criteria with recorded statuses: 5 met · 14 not met · 2 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
Absent from all gnomAD population databases including v2.1, v4.1, and gnomAD-Canada.
Located at serine 33, a critical GSK-3beta phosphorylation site within the N-terminal degradation domain of beta-catenin, identified as a statistically significant hotspot residue.
Functional studies demonstrate that p.Ser33Tyr causes gain-of-function through constitutive beta-catenin stabilization and enhanced TCF-mediated transcriptional activation, tested directly in T-LBL/ALL cell lines and Huh7 luciferase reporter assays.
Different pathogenic missense changes at the same codon (S33F, S33C) have been established as pathogenic in multiple independent publications across pilomatricomas, medulloblastomas, and T-cell malignancies.
In silico prediction tools (REVEL 0.495, BayesDel 0.0085, SpliceAI 0.00) do not support a damaging effect, though this is outweighed by the strong functional evidence.
This variant has been reported in somatic cancers 103 times in COSMIC and is classified as Oncogenic (gain-of-function) by OncoKB.
Applying generic ACMG/AMP 2015 combination rules: PS3 (strong) + PM1 (moderate) + PM2 (moderate) + PM5 (moderate) + BP4 (supporting benign) = 1 strong + 3 moderate pathogenic criteria minus 1 supporting benign criterion. This combination meets the threshold for Pathogenic classification.
No criteria match.
Met · 5
PS3 StrongThe exact variant p.Ser33Tyr has been directly tested in functional assays in at least two independent publications. Groen et al. (2008, PMID:18757411) identified S33Y in a primary T-LBL/ALL and demonstrated that S33Y h-catenin transfection into T-LBL/ALL cell lines enhanced TCF-mediated transcription and promoted cell growth. Pilati et al. (2014, PMID:24735922) tested S33Y in a TOP-FLASH luciferase reporter assay in Huh7 cells, confirming strong activation of beta-catenin transcriptional activity. Both studies demonstrate unequivocal gain-of-function: the variant disrupts the GSK-3beta phosphorylation site at serine 33, preventing ubiquitin-mediated degradation and causing constitutive beta-catenin stabilization and transcriptional activation. Details ▾Hide ▴
Evidence considered
- S33Y expression construct enhanced TCF-mediated transcription and promoted growth in T-LBL/ALL cell lines (PMID:18757411)
- S33Y activated TOP-FLASH luciferase reporter in Huh7 cells
- confirming beta-catenin stabilization and transcriptional activation (PMID:24735922)
- S33Y disrupts the GSK-3beta phosphorylation site (serine 33) in the N-terminal degradation domain
- a well-established mechanism of beta-catenin stabilization
Still missing
- Functional studies were performed in somatic cancer contexts
- no germline-specific functional data exist for this variant.
Sources
PM1 ModerateThe variant is located at codon 33 (serine 33), one of the four critical GSK-3beta phosphorylation sites (S33, S37, T41, S45) within the N-terminal degradation domain of beta-catenin (amino acids 29-49). This domain is essential for ubiquitin-mediated degradation of beta-catenin. Mutations at these residues are well-established to cause beta-catenin stabilization and constitutive WNT pathway activation. Cancer Hotspots identifies this residue as statistically significant. The N-terminal domain is a well-characterized functional domain critical to beta-catenin regulation. Details ▾Hide ▴
Evidence considered
- Residue S33 is a critical GSK-3beta phosphorylation site in the N-terminal degradation domain
- Cancer Hotspots: statistically significant hotspot residue
- PMID:10192393 describes the N-terminal segment as containing phosphorylation sites essential for ubiquitin-mediated degradation
Sources
PM2 ModerateThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 across all populations. The complete absence from large population databases supports pathogenicity. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (all populations)
- Absent from gnomAD v4.1 (all populations)
- Absent from gnomAD-Canada v1.0
Sources
PM5 ModerateMultiple different missense changes at codon 33 have been reported as pathogenic in the literature and ClinVar. Specifically, S33F (TCT→TTT) and S33C (TCT→TGT) are established pathogenic variants at the same residue. S33F was reported in pilomatricomas (PMID:10192393, 2 cases), medulloblastomas (PMID:16685513, 3 cases; PMID:16258095, codon 33 TCT→TTT; SER→PHE), and T-cell lymphoma (PMID:18757411, 1 case). S33C was reported in medulloblastomas (PMID:16685513, 2 cases). These same-residue comparator variants with different amino acid changes satisfy PM5 under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- S33F (TCT→TTT): reported as pathogenic in pilomatricomas (PMID:10192393
- n=2)
- medulloblastomas (PMID:16685513
- n=3
- PMID:16258095)
- and T-cell lymphoma (PMID:18757411
- n=1)
- S33C (TCT→TGT): reported as pathogenic in medulloblastomas (PMID:16685513
- All comparator variants are different missense changes at the same residue (codon 33) established as pathogenic in multiple independent publications
Sources
BP4 SupportingMultiple lines of computational evidence suggest a lack of deleterious effect. REVEL score is 0.495, below the typical 0.5 pathogenic threshold. BayesDel score is 0.0085, a very low value not consistent with damaging effect. SpliceAI max delta score is 0.00, indicating no predicted impact on splicing. While REVEL is borderline, the consensus of three independent in silico predictors leans toward a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.495 (borderline
- below 0.5 damaging threshold)
- BayesDel: 0.0085 (very low
- not consistent with damaging effect)
- SpliceAI: max delta 0.00 (no predicted splicing impact)
Sources
Not met · 14 · evaluated, threshold not reached
PS2 No de novo occurrence data were identified for NM_001098209.2:c.98C>A in any reviewed publication or database source. Confirmed de novo status requires parental testing, which is absent from the available evidence. Details ▾Hide ▴
Still missing
- No parental genotype data available for de novo confirmation.
PS4 No germline case-control data or observational cohort data are available for this variant. COSMIC reports 103 somatic observations, but these do not constitute germline case observations. No affected individual counts from clinical testing cohorts are available. Details ▾Hide ▴
Evidence considered
- COSMIC reports 103 somatic occurrences
- not applicable to germline PS4
Still missing
- No germline case counts or case-control studies available.
PM6 No de novo occurrence data were identified for NM_001098209.2:c.98C>A in any reviewed publication. Confirmed de novo status requires parental testing, which is absent from the available evidence. Details ▾Hide ▴
Still missing
- No parental genotype data available.
PP1 No cosegregation data are available for this variant. No family studies with affected and unaffected members were identified in the reviewed literature. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP2 While CTNNB1 has a significant number of pathogenic missense variants in exon 3, the primary germline disease mechanism for CTNNB1 syndrome (MIM 615075) is loss-of-function via nonsense and frameshift variants. Missense variants in exon 3 are predominantly associated with somatic gain-of-function in cancer. The HCI prior score is unavailable for CTNNB1. PP2 is not met under generic ACMG/AMP because missense is not the predominant mechanism for the established germline disease. Details ▾Hide ▴
Evidence considered
- CTNNB1 syndrome (MIM 615075) is predominantly caused by LOF nonsense/frameshift variants (PMID:41082542
- PMID:36083290)
- HCI prior score not available for CTNNB1
PP3 In silico prediction tools do not support a damaging effect for this variant. REVEL score is 0.495 (below the typical 0.5 threshold). BayesDel score is 0.0085 (very low, not consistent with pathogenicity). SpliceAI max delta score is 0.00 (no predicted splicing impact). Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.495 (below 0.5 damaging threshold)
- BayesDel: 0.0085 (low
- not consistent with damaging effect)
- SpliceAI: max delta 0.00 (no predicted splicing impact)
Sources
PP5 ClinVar reports this variant as Pathogenic (VariationID 17577) but with review status 'no assertion criteria provided' (1-star), submitted by OMIM via literature-only method with somatic origin. The global PP5 rule requires ClinVar 3-star expert panel review to apply at supporting strength. The current 1-star status does not meet the threshold for PP5 under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 17577: Pathogenic
- review status 'no assertion criteria provided'
- 2 OMIM somatic submissions
Sources
BA1 The variant is absent from all gnomAD populations (v2.1, v4.1, Canada v1.0). The allele frequency is 0.00, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0.00)
- Absent from gnomAD v4.1 (AF = 0.00)
Sources
BS1 The variant is absent from all gnomAD populations (v2.1, v4.1, Canada v1.0). The allele frequency is 0.00, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0.00)
- Absent from gnomAD v4.1 (AF = 0.00)
Sources
BS3 Multiple functional studies demonstrate that p.Ser33Tyr is a gain-of-function variant causing constitutive beta-catenin stabilization and transcriptional activation. In T-LBL/ALL cell lines, S33Y expression enhanced TCF-mediated transcription and promoted cell growth (PMID:18757411). In Huh7 cells, S33Y strongly activated a beta-catenin-driven luciferase reporter (PMID:24735922). These findings are consistent with a damaging, not benign, functional effect. Details ▾Hide ▴
Evidence considered
- S33Y enhanced TCF-mediated transcription and growth in T-LBL/ALL cells (PMID:18757411)
- S33Y activated TOP-FLASH luciferase reporter in Huh7 cells (PMID:24735922)
- Both studies demonstrate gain-of-function
- inconsistent with a benign effect
Sources
BS4 No cosegregation data are available for this variant. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP1 Although CTNNB1 syndrome (MIM 615075) is predominantly caused by truncating loss-of-function variants, the variant p.Ser33Tyr is located at a critical GSK-3beta phosphorylation site within the N-terminal degradation domain. Serine 33 is one of four residues whose phosphorylation is essential for beta-catenin ubiquitination and degradation. Missense changes at this residue are a well-established gain-of-function mechanism demonstrated in multiple functional studies. BP1 is not applied when the missense variant affects a known critical functional residue. Details ▾Hide ▴
Evidence considered
- S33 is a critical phosphorylation site for beta-catenin degradation (PMID:10192393)
- S33Y is a demonstrated gain-of-function variant (PMID:18757411
- PMID:24735922)
- BP1 exception: missense at a critical functional residue with demonstrated impact
Sources
BP5 The variant is reported as Pathogenic in ClinVar (VariationID 17577), not benign. BP5 requires a reputable source to report the variant as benign or likely benign, which is not the case here. Details ▾Hide ▴
PS5 The variant p.Ser33Tyr is reported as Pathogenic in ClinVar (VariationID 17577) but with review status 'no assertion criteria provided' (1-star), submitted by OMIM via literature-only method with somatic origin. This does not meet the 'reputable source' threshold required for PS5 under generic ACMG/AMP. Additionally, PS5 typically applies when a different nucleotide change produces the same amino acid change as a known pathogenic variant; no alternative nucleotide change exists for p.Ser33Tyr. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 17577: Pathogenic
- no assertion criteria provided
- OMIM somatic submission
Sources
Not assessed · 2 · no assessment recorded
PP4 No patient phenotype or specific clinical data were available for this case. PP4 requires phenotype specificity or family history consistent with the gene-associated condition. Details ▾Hide ▴
Still missing
- No patient phenotype data available for this case.
BS2 No data are available regarding observation of this variant in healthy adults. BS2 requires documented observation in a healthy adult individual with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- No healthy adult observational data available.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense substitutions. This is a missense variant (c.98C>A, p.Ser33Tyr), not a null variant (nonsense, frameshift, or canonical splice site). The generic PVS1 framework requires null-variant buckets; variant fell into 'other' bucket with apply_generic_pvs1_framework=false. Details ▾Hide ▴
No further detail was recorded.
PS1 N/APS1 requires a different nucleotide change producing the same amino acid change as a previously established pathogenic variant. At codon 33, TCT→TAT is the only nucleotide substitution yielding tyrosine; no alternative nucleotide change produces p.Ser33Tyr. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ANo evidence of observation in trans with a pathogenic variant. BP2 is not applicable in the absence of phase data. Details ▾Hide ▴
No further detail was recorded.
BP6 N/AClinVar reports this variant as Pathogenic, not benign. BP6 requires a reputable source to report the variant as benign. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_001098209.2:c.98C>A is a missense variant (p.Ser33Tyr), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001098209.2
- Coding (HGVS c.)
- NM_001098209.2:c.98C>A
- Protein (HGVS p.)
- NP_001091679.1:p.(Ser33Tyr)
- GRCh38
- chr3:41224610 C>A
- GRCh37
- chr3:41266101 C>A
- ClinVar
- 17577
- COSMIC
- COSV62688644
Gene diagram
Every interpreted variant in CTNNB1, mapped onto the exon structure of NM_001098209.2. Select a row to find it on the plot.
CTNNB1NM_001098209.2
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
- 0.495
- BayesDel
- 0.008
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest a lack of deleterious effect. REVEL score is 0.495, below the typical 0.5 pathogenic threshold. BayesDel score is 0.0085, a very low value not consistent with damaging effect. SpliceAI max delta score is 0.00, indicating no predicted impact on splicing. While REVEL is borderline, the consensus of three independent in silico predictors leans toward a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.495 (borderline
- below 0.5 damaging threshold)
- BayesDel: 0.0085 (very low
- not consistent with damaging effect)
- SpliceAI: max delta 0.00 (no predicted splicing impact)
Sources
PP3 In silico prediction tools do not support a damaging effect for this variant. REVEL score is 0.495 (below the typical 0.5 threshold). BayesDel score is 0.0085 (very low, not consistent with pathogenicity). SpliceAI max delta score is 0.00 (no predicted splicing impact). Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.495 (below 0.5 damaging threshold)
- BayesDel: 0.0085 (low
- not consistent with damaging effect)
- SpliceAI: max delta 0.00 (no predicted splicing impact)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_001098209.2:c.98C>A is a missense variant (p.Ser33Tyr), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.495. BayesDel score = 0.00849737.
8 paper records listed. 5 cited in the classification.
Cited in the classification
-
PMID 10192393 ↗A common human skin tumour is caused by activating mutations in beta-catenin.Chan EF et al. · 1999 AprS33Y (TCT→TAT) identified in 2 of 16 pilomatricomas. The N-terminal segment mutations, including S33Y, are activating mutations that disrupt GSK-3beta-dependent phosphorylation and ubiquitin-mediated degradation of beta-catenin, leading to constitutive WNT pathway activation.→ PM1 → PM5 Names this variant
Source detail
S33Y (TCT→TAT; found in two pilomatricomas)
Location Results (page 412); Figure 5a
Context Sanger sequencing of microdissected formalin-fixed paraffin-embedded pilomatricoma tissue, HinfI restriction endonuclease confirmation
-
PMID 16258095 ↗beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee.CTNNB1 codon 33 TCT→TAT (SER→TYR) mutation identified in 1 of 109 medulloblastomas with nuclear beta-catenin immunopositivity. Wnt/Wg pathway activation was an independent marker of favorable outcome in this cohort.→ PM5 Names this variant
Source detail
codon 33 TCT→TAT; SER→TYR
Location Results, paragraph on Mutational Analysis of CTNNB1 and APC (page 7953)
Context Direct DNA sequencing of FFPE medulloblastoma tissue from SIOP/UKCCSG PNET3 clinical trial
-
PMID 16685513 ↗Stratification of medulloblastoma on the basis of histopathological grading.CTNNB1 codon 33 TCT→TAT (Ser→Tyr) mutation identified in 1 of 146 medulloblastomas screened for beta-catenin exon 3 mutations. Overall, 10 of 146 (7%) medulloblastomas harbored CTNNB1 mutations.→ PM5 Names this variant
Source detail
33 TCT→TAT Ser→Tyr
Location Table 1 (page 9); Results section on beta-catenin mutations
Context PCR-SSCP and direct DNA sequencing of exon 3 of CTNNB1 from archival FFPE medulloblastoma tissue (SIOP II clinical trial)
-
PMID 18757411 ↗Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies.S33Y mutation identified in a primary precursor T-lymphoblastic lymphoma/leukemia (T-LBL/ALL). Functional characterization demonstrated that S33Y h-catenin transfection enhanced TCF-mediated transcription and promoted cell growth in T-LBL/ALL cell lines (CEM, Molt4, SupT1). The S33Y mutant is a gain-of-function variant that disrupts the GSK-3beta phosphorylation site.→ PS3 → PM1 Names this variant
Source detail
the h-catenin mutant S33Y, which was found in one of the primary T-LBL/ALLs described in this study...transfection of this h-catenin mutant markedly enhanced the growth of all three ALL cell lines
Location Results (page 6970, Fig. 2); Functional studies (pages 6972-6975, Fig. 5C)
Context TCF-reporter (TOPFLASH) luciferase assay and cell growth analysis in T-LBL/ALL cell lines (CEM, Molt4, SupT1) transfected with S33Y h-catenin expression construct
-
PMID 24735922 ↗Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation.S33Y CTNNB1 mutant tested as a comparator in TOP-FLASH luciferase reporter assay alongside K335I and N387K mutants in Huh7 hepatocellular cells. S33Y showed strong activation of beta-catenin transcriptional activity, confirming its gain-of-function properties. S33Y was used as a positive control representing classical exon 3 activating mutations.→ PS3 Names this variant
Source detail
CTNNB1 mutants S33Y (S33), T41A (T41), S45P (S45), K335I (K335), and N387K (N387) or control WT CTNNB1 (WT) and empty plasmid (EP) were transfected in Huh7 cells expressing a CTNNB1-driven luciferase (TOP-FLASH) reporter construct.
Location Results, Figure 4D; page 433
Context TOP-FLASH luciferase reporter assay in Huh7 hepatocellular carcinoma cell line
Other recorded publications
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PMID 17172831 ↗Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis.CTNNB1 mutations (D32Y, G34E, S37F) were identified in Wnt/Wg-active medulloblastomas associated with chromosome 6 loss and favorable prognosis. The specific variant p.Ser33Tyr was not identified in this cohort.Does not name this variant
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PMID 23852704 ↗Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.European Group on Tumor Markers 2014 guidelines update for biomarkers in colorectal cancer, gastric cancer, and gastrointestinal stromal tumors. The specific variant NM_001098209.2:c.98C>A (p.Ser33Tyr) was not identified in this guideline document.Does not name this variant
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PMID 9065402 ↗Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.Morin PJ et al. · 1997Morin et al. (1997) demonstrated that beta-catenin mutations in colon cancer cause constitutive activation of beta-catenin-Tcf signaling. Full text is not available in the case folder; only a screenshot (PNG) exists. The abstract discusses CTNNB1 mutations in colorectal cancers at the gene level. The specific variant p.Ser33Tyr could not be confirmed from the available material.Does not name this variant
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
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/17577/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41266101-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41224610-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-41224610-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001098209.2%3Ac.9…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/S33Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=223262257
- 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 = 17577)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.495. BayesDel score = 0.00849737.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62688644, n = 103 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.