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CTNNB1
Final classification
VUS
PM1PM2
CTNNB1
c.134C>A
p.Ser45Tyr
missense · exon 3
Gene context NCBI Gene ↗ OncoKB ↗

CTNNB1 encodes beta-catenin, a protein with dual roles in cell adhesion and gene regulation. It is part of the adherens junctions that maintain epithelial cell layers by controlling cell growth and cell-cell adhesion, and it also anchors the actin cytoskeleton and helps transmit the signal that stops cells from dividing once a tissue layer is complete. In the WNT signaling pathway, beta-catenin acts as a transcriptional activator that switches on growth-related genes such as Cyclin D1 and MYC. The gene is associated with colorectal cancer, pilomatrixoma, medulloblastoma, and ovarian cancer, and it acts as an oncogene: excessive beta-catenin activity is common in many solid tumors, including uterine, ovarian, liver, and colorectal cancers.

This variant

CTNNB1 encodes beta-catenin, whose Wnt-pathway overactivation drives multiple cancers, and Ser45 lies in the phosphodegron where missense changes stabilize the protein. Although p.(Ser45Tyr) sits at this oncogenic hotspot, germline CTNNB1 disease is predominantly loss-of-function, and without variant-specific functional or clinical evidence the classification remains Variant of Uncertain Significance.

Transcript
NM_001904.4
HGVS · transcript:coding
NM_001904.4:c.134C>A
GRCh38
chr3:41224646 C>A
GRCh37
chr3:41266137 C>A
Basis Variant of Uncertain Significance: only PM1 and PM2 (both moderate) are met, which reaches no ACMG/AMP Pathogenic or Benign combination under generic rules. ▾
Variant of Uncertain Significance: only PM1 and PM2 (both moderate) are met, which reaches no ACMG/AMP Pathogenic or Benign combination under generic rules.
Classification rationale
PM1PM2 VUS
CTNNB1 c.134C>A missense · exon 3

PM1 (Moderate): Ser45 is a conserved phospho-residue of the beta-catenin destruction-complex degron, a hotspot lacking benign variation. PM2 (Moderate): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases. With only PM1 and PM2 (both moderate) met, no Pathogenic or Benign ACMG/AMP combination is reached, so the variant is classified as Variant of Uncertain Significance.

PM1 + PM2 → VUS
Gene diagram · NM_001904.4 · variants mapped to exon structure
CTNNB1 NM_001904.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PM1 moderate review Pathogenic
Met (Moderate): Ser45 is a conserved phospho-residue of the beta-catenin degron, a functional hotspot lacking benign variation.
case_summary.json/evidence.json report that this variant lies in a statistically significant mutational hotspot per cancerhotspots.org (CTNNB1 S45 query), and COSMIC lists 55 independent somatic occurrences at this exact substitution (COSV62689938) -- both corroborating recurrence at this residue, though the underlying hotspots/COSMIC tools have no source_registry key to cite formally.PMID:12000790 (Amit et al. 2002) shows via mass spectrometry and phosphopeptide antibodies that an axin-CKI complex phosphorylates beta-catenin specifically at serine 45, and that this CKI phosphorylation event is necessary and sufficient to initiate the destruction cascade -- establishing S45 as a functionally indispensable residue.PMID:11955436 (Liu et al. 2002) identifies S33, S37, T41 and S45 as the conserved N-terminal phospho-degron residues whose mutation is the recurrent mechanism of beta-catenin stabilization in human cancers.
oncokb ↗PMID:11955436 ↗PMID:12000790 ↗PMID:41629672 ↗
✓
PM2 moderate Pathogenic
Met (Moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.
The normalized CTNNB1 NM_001904.4:c.134C>A (p.Ser45Tyr) variant was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.No CTNNB1-specific VCEP/ClinGen specification was retrieved; generic ACMG/AMP assessment is applicable.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 5 not met · 16 not assessed
Pathogenic
PS1 Not assessed: no independently classified pathogenic variant producing p.(Ser45Tyr) via another nucleotide change was found.
PS2 Not assessed: no proband phenotype or parental testing data were provided to evaluate a confirmed de novo occurrence.
PS3 Not assessed: the saturation genome editing screen reports only residue-level effects, not a result specific to p.Ser45Tyr.
PS4 Not assessed: no case-control comparison or enrichment analysis for this exact variant was available.
PM3 Not assessed: no affected individual with a second pathogenic allele or phase data was documented.
PM5 Not assessed: no independently classified pathogenic substitution at Ser45 was available as a comparator.
PM6 Not assessed: no reported de novo occurrence or parental genotypes were available.
PP1 Not assessed: no pedigree or family genotype data were provided to evaluate co-segregation.
PP3 Not met: REVEL 0.353 falls below the calibrated >=0.644 PP3 threshold.
PP4 Not assessed: no phenotype or diagnostic workup evidence specific to a CTNNB1-related germline disorder was available.
PP5 Not assessed: the ClinVar record has no expert-panel assertion, only a somatic laboratory submission.
Benign
BA1 Not met: absent from gnomAD, so population frequency is far below the >1% BA1 threshold.
BS1 Not met: absent from gnomAD, with no population frequency exceeding that expected for a CTNNB1-associated disorder.
BS2 Not assessed: no unaffected adult carrier or homozygote observations with phenotype and age data were supplied.
BS3 Not assessed: no functional assay result for p.Ser45Tyr showing normal function was available.
BS4 Not assessed: no unaffected carriers or other informative non-segregation observations were provided.
BP1 Not met: despite loss-of-function being the germline disease mechanism, Ser45 is a documented oncogenic hotspot with functional evidence of missense pathogenicity.
BP2 Not assessed: no observation of the variant in cis or in trans with a pathogenic variant was documented.
BP4 Not met: REVEL 0.353 exceeds the calibrated <=0.290 BP4 threshold, in the indeterminate zone.
BP5 Not assessed: no evidence of an alternative molecular diagnosis fully explaining the phenotype was available.
BP6 Not assessed: the ClinVar record has no expert-panel benign or likely benign assertion.
N/A · 5 PVS1 · PM4 · PP2 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4530134)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.353. BayesDel score = 0.104857.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62689938, n = 55 times).
Hotspots
This variant lies in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 4 further PMIDs triaged but not cited — see Sources & references.
Rule & framework references · cited for criterion definitions, not variant evidence
11955436 ↗ Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.
12000790 ↗ Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway.
41629672 ↗ Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on s
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 4 PMIDs not cited in assessment
9419974 ↗ Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin. ONCOKB
16909133 ↗ Genetic and epigenetic alterations on the short arm of chromosome 11 are involve ONCOKB
25190313 ↗ Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distin ONCOKB
24332040 ↗ Targeting oxidative stress in embryonal rhabdomyosarcoma. CLINVAR