NM_001904.3:c.101_102delGAinsTT

CTNNB1 · NP_001895.1:p.(Gly34Val) · NM_001904.3

GRCh37: chr3:41266104 GA>TT · GRCh38: chr3:41224613 GA>TT

Gene: CTNNB1 Transcript: NM_001904.3

Final call

VUS

PM1 moderate PM2 moderate

Variant details

Gene

CTNNB1

Transcript

NM_001904.3

Protein

NP_001895.1:p.(Gly34Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not assessed	No de novo occurrence data are available for this variant.
PS3	Not met	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.
PS4	Not assessed	No case-control or prevalence data are available comparing affected versus unaffected individuals.
PS5	Not met	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.	oncokb
PM1	Met	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	This 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.
PM5	N/A	This 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.	pm5_candidates
PM6	Not assessed	No de novo occurrence data are available. PM6 requires a de novo observation with confirmed maternity and paternity.
PP1	Not assessed	No segregation data are available for this variant.
PP2	N/A	PP2 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.
PP3	Not assessed	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.	spliceai
PP4	Not assessed	No patient phenotype or clinical data are available for evaluation of phenotype specificity.
PP5	Not met	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.	oncokb clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available on observation of this variant in healthy adult individuals for a fully penetrant disorder.
BS3	Not met	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.
BS4	Not assessed	No segregation data are available to assess lack of cosegregation with disease.
BP1	Not met	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.
BP2	Not assessed	No data are available on observation of this variant in trans with a known pathogenic variant.
BP3	Not met	The variant does not lie within a repetitive region. BP3 applies to in-frame deletions or insertions in repetitive regions without a known function.
BP4	Not assessed	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.	spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	This 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.