Variant classification summary

NM_001904.4:c.1149G>T

CTNNB1 · NP_001895.1:p.(Trp383Cys) · NM_001904.4

GRCh37: chr3:41274899 G>T · GRCh38: chr3:41233408 G>T

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM2 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Trp383Cys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The CTNNB1 c.1149G>T (p.Trp383Cys) variant has been observed in somatic cancers 12 times in COSMIC and has also been reported in ClinVar, although ClinVar submission-level classification details were not available from the retrieved record.

2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, placing its observed population frequency at 0, below the 0.1% rarity threshold used for PM2.

3

In a published functional study of CTNNB1 armadillo repeat 5 and 6 substitutions, residue W383 was identified as recurrently mutated in cancer, and substitutions in this region were associated with reduced APC binding and increased downstream beta-catenin signaling, but direct functional testing of p.Trp383Cys was not established from the retrieved evidence.

4

Computational findings are concerning for a missense effect, with REVEL 0.642 and BayesDel 0.287483, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.02.

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 is a missense variant, and it does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants.	pvs1_variant_assessment pvs1_generic_framework pvs1_gene_context
PS1	Not assessed	No evidence was identified showing that this nucleotide change creates the same amino acid change as a previously established pathogenic variant.
PS2	Not assessed	No confirmed de novo occurrence data were identified for this variant.
PS3	Not assessed	A published study showed that CTNNB1 substitutions in armadillo repeats 5 and 6 can reduce APC binding and increase downstream signaling, but direct well-established functional testing of p.Trp383Cys was not established from the retrieved evidence.	PMID:31857074 oncokb
PS4	Not met	This variant has been observed in somatic cancers and has a ClinVar record, but no germline case-control enrichment or statistically increased prevalence in affected individuals was identified.	clinvar
PM1	Not assessed	Residue W383 lies in a recurrently mutated CTNNB1 cancer region, but the available evidence does not establish a germline disease-specific mutational hotspot or critical benign-variation-depleted region suitable for applying PM1 with confidence.	PMID:31857074 hotspots
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, so the observed population frequency is 0 and is below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	No recessive context or trans observations relevant to PM3 were identified for this variant.
PM4	N/A	This is not a protein length-changing variant, so PM4 does not apply.
PM5	N/A	Classic same-residue PM5 logic could not be confirmed safely for this case, and no validated same-residue pathogenic comparator was identified for use.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	No gene-specific evidence framework was available to support applying PP2 for this CTNNB1 missense variant.
PP3	Not assessed	Computational results are concerning for a missense effect, with REVEL 0.642 and BayesDel 0.287483, while SpliceAI predicts no significant splice impact with a max delta score of 0.02; however, without a gene-specific computational rule or clearly prespecified threshold for this case, these data were not used alone to apply PP3.	revel bayesdel spliceai
PP4	Not assessed	No phenotype data were provided to assess whether the clinical presentation is highly specific for a CTNNB1-related disorder.
PP5	N/A	PP5 is not applied in current ACMG/AMP interpretation practice.
BA1	Not met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, so the observed population frequency is 0 and is far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, so the observed population frequency is 0 and does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a context sufficient to apply BS2.
BS3	Not met	Available functional literature does not show a normal or benign effect for this variant.	PMID:31857074 oncokb
BS4	Not assessed	No data were identified showing lack of segregation with disease.
BP1	Not assessed	BP1 was not applied because no gene-specific framework was available to determine whether this CTNNB1 missense change should be treated as a low-prior-probability missense mechanism.	pvs1_gene_context
BP2	Not assessed	No phase data with another variant were identified.
BP3	N/A	This is not an in-frame insertion/deletion in a repetitive region, so BP3 does not apply.
BP4	Not met	Benign computational evidence was not identified. REVEL is 0.642 and BayesDel is 0.287483, which do not support a benign missense interpretation, although SpliceAI predicts no significant splice impact with a max delta score of 0.02.	revel bayesdel spliceai
BP5	Not assessed	No alternative molecular explanation was identified to support BP5.
BP6	N/A	BP6 is not applied in current ACMG/AMP interpretation practice.
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic change, so BP7 does not apply.	spliceai

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.