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CTNNB1c.101_102delinsTTUncertain significance
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Variant interpretation report

CTNNB1 c.101_102delinsTT, p.(Gly34Val)

NM_001904.3:c.101_102delinsTT NP_001895.1:p.(Gly34Val) 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate

This variant alters codon 34 (Gly34Val) within the CTNNB1 exon 3 degron hotspot (residues 31-48), a well-established mutational hotspot and critical functional domain for β-TRCP binding and β-catenin degradation. The residue lies in a statistically significant CancerHotspots region.

PM2Moderate
PM2 · moderate

This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, well below the PM2 threshold of 0.1% allele frequency.

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 moderate, PM2 moderate; combination = 2 moderate, 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
0.080 maximum delta

Recorded SpliceAI maximum delta score: 0.080. 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: Gain-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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.

28 criteria with recorded statuses: 2 met · 10 not met · 11 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001904.3:c.101_102delGAinsTT (p.Gly34Val) is an in-frame indel in exon 3 of CTNNB1, within the well-established β-catenin degron hotspot (PM1).

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2).

The variant is absent from ClinVar and has no germline classification from any reputable source.

OncoKB classifies this variant as Likely Oncogenic based on somatic cancer context; this does not constitute a germline pathogenicity assertion.

No functional studies have been performed on the specific c.101_102delinsTT indel. The G34V protein change has been observed via SNV in somatic cancers (HCC, medulloblastoma) and demonstrates gain-of-function through impaired β-catenin degradation, but this mechanism does not clearly support germline loss-of-function pathogenicity for CTNNB1 syndrome (PS3 not met).

SpliceAI predicts no significant splice impact (max delta score = 0.08), and REVEL/BayesDel scores are unavailable for this indel (PP3 not assessed).

Two moderate criteria (PM1 + PM2) are met. Under ACMG/AMP 2015 combination rules, two moderate criteria alone do not reach the threshold for Likely Pathogenic (requires ≥3 moderate, or 1 strong + 1-2 moderate, or 2 moderate + ≥2 supporting). This variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM1 ModerateThis variant alters codon 34 (Gly34Val) within the CTNNB1 exon 3 degron hotspot (residues 31-48), a well-established mutational hotspot and critical functional domain for β-TRCP binding and β-catenin degradation. The residue lies in a statistically significant CancerHotspots region. Details ▾Hide ▴
Evidence considered
  • Alters Gly34 in the CTNNB1 degron hotspot
  • CancerHotspots confirms statistically significant enrichment of mutations at this residue.
Sources
oncokb ↗
PM2 ModerateThis variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, well below the PM2 threshold of 0.1% allele frequency. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • gnomAD v4.1 (0 alleles)
  • gnomAD-Canada (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 10 · evaluated, threshold not reached

PS1 The same amino acid change (G34V) has been observed via SNV in somatic cancer (medulloblastoma, HCC) but is not established as a germline pathogenic variant in ClinVar or the literature. No prior germline classification exists for G34V via any nucleotide change. Details ▾Hide ▴
Evidence considered
  • G34V has been observed as a somatic SNV in cancer but has no germline pathogenic classification in ClinVar.
Still missing
  • No established germline pathogenic variant with the same amino acid change.
Sources
clinvar ↗
PS3 Functional evidence from somatic cancer studies demonstrates that G34V (via SNV) impairs β-catenin degradation, leading to gain-of-function and Wnt pathway activation. This gain-of-function mechanism does not clearly support pathogenicity for the germline loss-of-function disease mechanism associated with CTNNB1 syndrome. Moreover, no well-established functional assay has been performed on the specific indel variant. Details ▾Hide ▴
Evidence considered
  • G34V in somatic contexts shows β-catenin stabilization and Wnt pathway activation (gain-of-function). No functional data on the indel specifically or in a germline disease model.
Still missing
  • No functional studies performed on the specific c.101_102delinsTT variant
  • somatic gain-of-function evidence does not clearly translate to germline LOF pathogenicity.
PP5 OncoKB classifies the variant as 'Likely Oncogenic' but this is a somatic cancer designation. No reputable germline source has classified this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • OncoKB Likely Oncogenic (somatic)
  • absent from ClinVar.
Sources
oncokb ↗clinvar ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases (AF = 0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases (AF = 0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 Available functional evidence demonstrates that G34V (via SNV) is activating (gain-of-function), leading to β-catenin stabilization and Wnt pathway activation. This does not support a benign effect; the evidence conflicts with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • G34V SNV shows β-catenin stabilization in HuH6 cells (PMID:9671767)
  • no evidence of normal function.
BP1 CTNNB1 germline disease (CTNNB1 syndrome / neurodevelopmental disorder with spastic diplegia and visual defects) is associated with both truncating and missense variants. Missense variants in CTNNB1 are established as germline pathogenic. Details ▾Hide ▴
Evidence considered
  • CTNNB1 syndrome is caused by both missense and truncating germline variants (PMID:33350591
  • PMID:36083290).
BP3 The variant does not lie within a repetitive region. BP3 applies to in-frame deletions or insertions in repetitive regions without a known function. Details ▾Hide ▴
Evidence considered
  • Variant is in the CTNNB1 degron motif
  • a critical functional domain
  • not a repetitive region.
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification from any source.
Sources
clinvar ↗
PS5 OncoKB classifies this variant as 'Likely Oncogenic' but this is a somatic cancer designation, not a germline pathogenicity assertion. No reputable source has classified this variant as germline pathogenic. Details ▾Hide ▴
Evidence considered
  • OncoKB Likely Oncogenic (somatic context only).
Sources
oncokb ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo occurrence data are available for this variant. Details ▾Hide ▴
Still missing
  • No parental testing or de novo data available.
PS4 No case-control or prevalence data are available comparing affected versus unaffected individuals. Details ▾Hide ▴
Still missing
  • No case-control studies available.
PM6 No de novo occurrence data are available. PM6 requires a de novo observation with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP3 REVEL and BayesDel scores are not available for indels. SpliceAI predicts no significant splice impact (max delta score = 0.08). No computational pathogenicity predictors are applicable to this in-frame indel. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.08 (no splice impact). REVEL/BayesDel unavailable for indels.
Still missing
  • No in silico missense pathogenicity predictors available for indels.
Sources
spliceai ↗
PP4 No patient phenotype or clinical data are available for evaluation of phenotype specificity. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided.
BS2 No data are available on observation of this variant in healthy adult individuals for a fully penetrant disorder. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data available.
BS4 No segregation data are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data available.
BP2 No data are available on observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
  • No trans configuration data available.
BP4 SpliceAI predicts no significant splice impact (max delta score = 0.08), but comprehensive in silico predictors for indels are not available. Limited evidence for BP4 application. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.08 (no splice impact). Other in silico predictors unavailable for indels.
Still missing
  • No comprehensive in silico predictors for indel pathogenicity.
Sources
spliceai ↗
BP5 No data are available regarding an alternate molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis in-frame indel (c.101_102delinsTT) produces a single amino acid substitution (p.Gly34Val) rather than a null variant. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
  • In-frame deletion-insertion resulting in missense change G34V
  • no premature termination or splice consensus disruption.
Sources
pvs1_generic_framework ↗
PM4 N/AThis is an in-frame indel (2 bp deleted, 2 bp inserted) resulting in a single amino acid substitution (Gly34Val) with no net change in protein length. PM4 applies to in-frame deletions or insertions that alter protein length in a nonrepeat region. Details ▾Hide ▴
Evidence considered
  • In-frame change producing G34V missense substitution
  • no protein length change.
PM5 N/AThis is an indel, not a missense variant reached by a single nucleotide substitution. PM5 requires a novel missense change at the same residue as a known pathogenic missense variant. Automated PM5 candidate harvesting was skipped for this variant. Details ▾Hide ▴
Evidence considered
  • Indel variant
  • not eligible for classic PM5 assessment.
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is an indel, and CTNNB1 has abundant missense variation in cancer contexts. Details ▾Hide ▴
Evidence considered
  • Indel variant
  • PP2 is specific to missense variants.
BP7 N/AThis is an in-frame indel producing a missense amino acid change (Gly34Val), not a synonymous variant. SpliceAI predicts no significant splice impact (max delta 0.08), but BP7 applies only to synonymous variants. Details ▾Hide ▴
Evidence considered
  • Non-synonymous in-frame indel producing G34V.

Identifiers

Gene
CTNNB1
Transcript
NM_001904.3
Coding (HGVS c.)
NM_001904.3:c.101_102delinsTT
Protein (HGVS p.)
NP_001895.1:p.(Gly34Val)
GRCh38
chr3:41224613 GA>TT
GRCh37
chr3:41266104 GA>TT

Gene diagram

Every interpreted variant in CTNNB1, mapped onto the exon structure of NM_001904.3. Select a row to find it on the plot.

CTNNB1NM_001904.3
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 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

SpliceAI acceptor lossat -87 bp
0.000
SpliceAI acceptor gainat +27 bp
0.080
SpliceAI donor lossat +41 bp
0.000
SpliceAI donor gainat -292 bp
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 REVEL and BayesDel scores are not available for indels. SpliceAI predicts no significant splice impact (max delta score = 0.08). No computational pathogenicity predictors are applicable to this in-frame indel. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.08 (no splice impact). REVEL/BayesDel unavailable for indels.
Still missing
  • No in silico missense pathogenicity predictors available for indels.
Sources
spliceai ↗
BP4 SpliceAI predicts no significant splice impact (max delta score = 0.08), but comprehensive in silico predictors for indels are not available. Limited evidence for BP4 application. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.08 (no splice impact). Other in silico predictors unavailable for indels.
Still missing
  • No comprehensive in silico predictors for indel pathogenicity.
Sources
spliceai ↗
BP7 N/AThis is an in-frame indel producing a missense amino acid change (Gly34Val), not a synonymous variant. SpliceAI predicts no significant splice impact (max delta 0.08), but BP7 applies only to synonymous variants. Details ▾Hide ▴
Evidence considered
  • Non-synonymous in-frame indel producing G34V.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).

4 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

  • Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables.
    G34V is reported as a somatic SNV (34gga>gta) in two medulloblastoma tumors with Wnt pathway activation. The specific indel NM_001904.3:c.101_102delGAinsTT is not described in this paper.
    Does not name this variant
    PMID 20921458 ↗
    Quoted passage
    W&S mut (34gga>gta) Polysomy No No Polysomy Classic M2 ADF

    Table 3 (34gga>gta mutations in W&S and P&S β-catenin nucleopositive tumors)

  • Targeted Molecular Analysis in Adrenocortical Carcinomas: A Strategy Toward Improved Personalized Prognostication.
    Describes targeted molecular analysis in adrenocortical carcinoma for prognostic stratification. CTNNB1 and the variant NM_001904.3:c.101_102delGAinsTT are not discussed in the abstract.
    Does not name this variant
    PMID 30113656 ↗
  • Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling.
    Saturation genome editing study of all 342 possible missense substitutions in the CTNNB1 exon 3 hotspot. The study quantifies Wnt signaling activation for G34V missense via SNV but does not include or study indel variants such as c.101_102delGAinsTT.
    Does not name this variant
    PMID 41629672 ↗
  • Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas.
    G34V is reported as an activating somatic point mutation in two human HCC tumors and the HuH6 hepatoma cell line, leading to β-catenin accumulation in both cytoplasm and nucleus. The specific indel NM_001904.3:c.101_102delGAinsTT is not described in this paper.
    Does not name this variant
    PMID 9671767 ↗
    Quoted passage
    The mutation G34V, observed in the Huh6 hepatoma cell line, led to accumulation of β-catenin both in the cytoplasm and nucleus

    Table 1 (G34V point mutations in human HCC and HuH6 cell line); Results, paragraph on point mutations; Figure 3

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 0.080 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

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 is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant lies in a statistically significant hotspot.