0%
CTNNB1c.98C>TUncertain significance
Print report
Variant interpretation report

CTNNB1 c.98C>T, p.(Ser33Phe)

NM_001098209.2:c.98C>T NP_001091679.1:p.(Ser33Phe) View identifiers
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.

About CTNNB1

No gene-level summary was recorded for this case.

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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Supporting
PS3 · supporting

Functional studies demonstrate that the S33F substitution disrupts the GSK-3β phosphorylation degron motif in β-catenin, leading to protein stabilization and nuclear accumulation. In colorectal cancer tissue harboring this mutation, immunohistochemistry confirmed increased β-catenin protein expression in tumor cells versus normal adjacent tissue. S33 is a well-characterized phosphorylation site whose mutation activates canonical Wnt signaling.

PM1Moderate
PM1 · moderate

The variant alters serine 33, a critical residue within the GSK-3β phosphorylation degron motif (residues 33-45) of β-catenin. This is a well-established functional domain where missense mutations cause constitutive Wnt pathway activation. The residue is identified as a statistically significant mutational hotspot in cancer.

PM2Moderate
PM2 · moderate

The variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, consistent with a variant not tolerated in the general population.

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: PS3 supporting, PM1 moderate, PM2 moderate; combination = 2 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.

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
1 reported laboratory submissions

1 other.

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: Likely Oncogenic.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
199 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV62688300, n = 199 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 13 not met · 3 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM1 (moderate): The variant alters serine 33, a critical GSK-3β phosphorylation residue within the N-terminal degron motif of β-catenin — a well-established functional domain where missense mutations cause constitutive Wnt pathway activation. The residue is identified as a statistically significant mutational hotspot.

PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a variant not tolerated in the general population.

PS3 (supporting): Functional studies demonstrate that S33F disrupts GSK-3β phosphorylation, leading to β-catenin stabilization and nuclear accumulation. In colorectal cancer tissue, the mutation was confirmed to cause increased β-catenin protein expression.

The combined evidence (PM1 + PM2 + PS3) yields two moderate and one supporting criterion. Per ACMG/AMP 2015 generic combination rules (PMID:25741868), this does not reach the Likely Pathogenic threshold, which requires ≥3 moderate or ≥2 moderate plus ≥2 supporting criteria. The variant is classified as a Variant of Uncertain Significance (VUS).

This variant (S33F) is a well-established somatic oncogenic driver in multiple cancer types (COSMIC count: 199; pilomatricoma, medulloblastoma, colorectal cancer, hepatocellular carcinoma) but has not been reported as a germline disease-causing variant. It is absent from population databases. Germline CTNNB1 syndrome is primarily associated with loss-of-function truncating variants, not the exon 3 degron missense mutations that characterize somatic oncogenesis.

Met · 3

PS3 SupportingFunctional studies demonstrate that the S33F substitution disrupts the GSK-3β phosphorylation degron motif in β-catenin, leading to protein stabilization and nuclear accumulation. In colorectal cancer tissue harboring this mutation, immunohistochemistry confirmed increased β-catenin protein expression in tumor cells versus normal adjacent tissue. S33 is a well-characterized phosphorylation site whose mutation activates canonical Wnt signaling. Details ▾Hide ▴
Evidence considered
  • Alomar et al. (2016) demonstrated S33F causes β-catenin nuclear accumulation in colorectal cancer via IHC.
  • OncoKB classifies S33F as Likely Oncogenic with Gain-of-function mechanism.
  • S33 is a known GSK-3β phosphorylation site in the β-catenin degron motif
  • substitution abrogates phosphorylation-dependent degradation.
Sources
PMID:27543871 ↗oncokb ↗27543871
PM1 ModerateThe variant alters serine 33, a critical residue within the GSK-3β phosphorylation degron motif (residues 33-45) of β-catenin. This is a well-established functional domain where missense mutations cause constitutive Wnt pathway activation. The residue is identified as a statistically significant mutational hotspot in cancer. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots identifies S33 as a statistically significant hotspot residue.
  • S33 is a GSK-3β phosphorylation site within the N-terminal degron motif critical for β-catenin degradation.
  • Chang et al. (2015) identify CTNNB1 as harboring recurrent hotspot mutations.
Sources
PMID:27543871 ↗PMID:26619011 ↗2754387126619011
PM2 ModerateThe variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, consistent with a variant not tolerated in the general population. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 13 · evaluated, threshold not reached

PS2 No de novo occurrence with confirmed maternity and paternity has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No published de novo reports with confirmed parentage were identified.
Still missing
  • No segregation or de novo studies available.
PS4 No systematic case-control study comparing variant prevalence in affected individuals versus controls has been conducted. The variant is absent from gnomAD, but no statistically significant enrichment in a well-defined patient cohort is available. Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD v2.1 and v4.1. No case-control enrichment data available.
Still missing
  • No case-control or cohort enrichment study available.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM6 No de novo occurrence (without confirmation of maternity/paternity) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No published de novo reports were identified.
Still missing
  • No de novo studies available.
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation studies identified.
Still missing
  • No segregation data available.
PP3 In silico predictions are mixed and do not provide consistent support for pathogenicity. REVEL score is 0.534 (borderline), BayesDel score is 0.150 (low, favoring benign), and SpliceAI predicts no splice impact (max delta 0.00). Multiple computational lines do not converge on a pathogenic prediction. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.534 (borderline pathogenic).
  • BayesDel score: 0.150 (low
  • favoring benign).
  • SpliceAI max delta: 0.00 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
PP5 ClinVar lists this variant under variation ID 17583 with an aggregate classification of 'other' and review status 'no assertion criteria provided.' All four ClinVar submissions lack assertion criteria; two OMIM submissions classify as Pathogenic but are derived from literature only with somatic origin. No clinical diagnostic laboratory with supporting criteria has reported this variant as pathogenic for germline disease. Details ▾Hide ▴
Evidence considered
  • ClinVar variation ID 17583: classification 'other'
  • review status 'no assertion criteria provided.'
  • All four ClinVar submissions lack ACMG assertion criteria and report somatic origin.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1 and v4.1. The allele frequency is 0%, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD, with an allele frequency well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation of this variant in healthy adult individuals has been documented. The variant is absent from gnomAD, providing no evidence for benign occurrence in trans with a pathogenic variant or in unaffected controls. Details ▾Hide ▴
Evidence considered
  • Variant absent from population databases
  • no healthy adult carriers documented.
Still missing
  • No data on observation in healthy adults.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Well-established functional studies demonstrate that S33F has a gain-of-function activating effect, not a benign effect. The substitution disrupts the GSK-3β phosphorylation degron, leading to β-catenin stabilization and constitutive Wnt signaling. Details ▾Hide ▴
Evidence considered
  • S33F leads to β-catenin nuclear accumulation (activating effect
  • not benign).
  • OncoKB classifies as Likely Oncogenic
  • Gain-of-function.
Sources
PMID:27543871 ↗oncokb ↗27543871
BS4 No segregation data are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family segregation studies available.
BP4 Computational evidence is mixed and does not provide multiple consistent lines supporting a benign effect. REVEL (0.534) is borderline pathogenic. BayesDel (0.150) is low but not definitively benign. SpliceAI predicts no splice impact, but this alone is insufficient for BP4 in the context of a missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.534 (not clearly benign).
  • BayesDel score: 0.150 (low
  • lean benign but not strongly).
  • SpliceAI max delta: 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP6 No reputable source reports this variant as benign. ClinVar classification is 'other' with no assertion criteria provided. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: 'other
  • ' no benign assertion from any submitter.
Sources
clinvar ↗

Not assessed · 3 · no assessment recorded

PP2 CTNNB1 germline disease (CTNNB1 syndrome) is primarily caused by truncating variants, while missense variants in the degron motif are characterized as somatic oncogenic drivers. The gene's germline missense constraint metrics were not evaluated in this assessment. Details ▾Hide ▴
Still missing
  • gnomAD missense constraint (Z-score) not evaluated.
PP4 No patient phenotype or family history information was provided for this case. Details ▾Hide ▴
Still missing
  • No patient phenotype data available.
PS5 No evidence for an alternate molecular basis of disease in a patient carrying this variant was identified. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses in carriers.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.98C>T, p.S33F). PVS1 is applicable only to null variants (nonsense, frameshift, canonical ±1,2 splice sites). The pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false. Details ▾Hide ▴
Evidence considered
  • Missense substitution does not qualify for PVS1 null-variant framework (PMC6185798).
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo alternative nucleotide change at codon 33 resulting in the same p.S33F amino acid substitution has been identified. The only route to phenylalanine from serine at this position is c.98C>T. Details ▾Hide ▴
Evidence considered
  • No alternative nucleotide change producing the same S33F missense has been reported.
PM5 N/ANo same-residue comparator variant with a different pathogenic missense change was identified in ClinVar. The pm5_candidates harvest found zero eligible candidates. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variants available.
Sources
pm5_candidates
BP1 N/AMissense variants in the CTNNB1 degron motif are a well-established mechanism of pathogenicity (gain-of-function). BP1 applies only when missense variants are not a known disease mechanism for the gene. Details ▾Hide ▴
Evidence considered
  • CTNNB1 missense variants in the GSK-3β phosphorylation degron are established gain-of-function oncogenic drivers.
Sources
PMID:27543871 ↗oncokb ↗27543871
BP2 N/ANo observation in trans with a pathogenic variant in a dominant disorder has been reported. No data available to evaluate this criterion. Details ▾Hide ▴
Evidence considered
  • No trans-observation data available.
BP5 N/ANo alternate molecular basis for disease has been identified in a patient carrying this variant. Details ▾Hide ▴
Evidence considered
  • No data on alternate molecular diagnoses.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.98C>T, p.S33F), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Identifiers

Gene
CTNNB1
Transcript
NM_001098209.2
Coding (HGVS c.)
NM_001098209.2:c.98C>T
Protein (HGVS p.)
NP_001091679.1:p.(Ser33Phe)
GRCh38
chr3:41224610 C>T
GRCh37
chr3:41266101 C>T
ClinVar
17583
COSMIC
COSV62688300

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.534
BayesDel
0.150

How the predictions were used

PP3 In silico predictions are mixed and do not provide consistent support for pathogenicity. REVEL score is 0.534 (borderline), BayesDel score is 0.150 (low, favoring benign), and SpliceAI predicts no splice impact (max delta 0.00). Multiple computational lines do not converge on a pathogenic prediction. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.534 (borderline pathogenic).
  • BayesDel score: 0.150 (low
  • favoring benign).
  • SpliceAI max delta: 0.00 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
BP4 Computational evidence is mixed and does not provide multiple consistent lines supporting a benign effect. REVEL (0.534) is borderline pathogenic. BayesDel (0.150) is low but not definitively benign. SpliceAI predicts no splice impact, but this alone is insufficient for BP4 in the context of a missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.534 (not clearly benign).
  • BayesDel score: 0.150 (low
  • lean benign but not strongly).
  • SpliceAI max delta: 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.98C>T, p.S33F), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.534. BayesDel score = 0.149736.

8 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

  • β-Catenin accumulation and S33F mutation of CTNNB1 gene in colorectal cancer in Saudi Arabia.
    No paper-specific finding is recorded.
    PMID 27543871 ↗
  • Stratification of medulloblastoma on the basis of histopathological grading.
    No paper-specific finding is recorded.
    PMID 16685513 ↗
  • Chromosome instability in human hepatocellular carcinoma depends on p53 status and aflatoxin exposure.
    No paper-specific finding is recorded.
    PMID 18467159 ↗
  • Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
    No paper-specific finding is recorded.
    PMID 26619011 ↗
  • Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling.
    No paper-specific finding is recorded.
    PMID 41629672 ↗
  • A common human skin tumour is caused by activating mutations in beta-catenin.
    Chan EF et al. · 1999
    No paper-specific finding is recorded.
    PMID 10192393 ↗
  • The genetic landscape of the childhood cancer medulloblastoma.
    Parsons DW et al. · 2011
    No paper-specific finding is recorded.
    PMID 21163964 ↗
  • Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways.
    Shukla N et al. · 2012
    No paper-specific finding is recorded.
    PMID 22142829 ↗

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 other 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

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.

ClinVar

This variant has been reported in ClinVar as other (1 clinical laboratory). (ClinVarID = 17583)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.534. BayesDel score = 0.149736.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: 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; COSV62688300, n = 199 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.