Variant classification summary

NM_001904.4:c.1648C>T

CTNNB1 · NP_001895.1:p.(Arg550Cys) · NM_001904.4

GRCh37: chr3:41275753 C>T · GRCh38: chr3:41234262 C>T

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM2 moderate

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Arg550Cys)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The CTNNB1 c.1648C>T (p.Arg550Cys; p.R550C) variant has been reported in ClinVar as a variant of uncertain significance by a single submitter.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting PM2 under the generic ACMG framework.

3

Available computational evidence is mixed: SpliceAI predicts no significant splice effect with a maximum delta score of 0.05, while REVEL is 0.507 and BayesDel is 0.164625, so the in silico data support neither PP3 nor BP4.

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 missense variant, NM_001904.4:c.1648C>T (p.Arg550Cys; p.R550C), does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 was not assessed.
PS2	Not assessed	No confirmed de novo occurrence of this variant with a consistent phenotype and documented parental relationships was identified, so PS2 was not assessed.
PS3	Not assessed	No well-established functional study of this exact variant was identified showing a damaging effect, so PS3 was not assessed.	oncokb
PS4	Not assessed	Available evidence does not show that this variant is significantly enriched in affected individuals compared with controls, so PS4 was not assessed.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available evidence does not show that codon 550 lies in a well-established mutational hotspot or a critical domain without benign variation. Cancer Hotspots did not identify this residue as a statistically significant hotspot, and available curated somatic context did not provide variant-specific hotspot support.	hotspots oncokb
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the non-VCEP PM2 threshold of 0.1%, supporting rarity in the general population.	gnomad_v2 gnomad_v4
PM3	N/A	No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive context, so PM3 is not applicable to the available evidence.
PM4	N/A	This is a missense substitution and does not cause a protein length change from an in-frame insertion, deletion, or stop-loss event, so PM4 is not applicable.
PM5	Not met	No pathogenic or likely pathogenic missense comparator at the same residue was identified in the available evidence, and automated candidate review did not find usable same-residue comparators, so PM5 is not met.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence of this variant without full parental confirmation was identified, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.
PP2	Not assessed	Available evidence does not provide a gene-specific missense-constraint framework for applying PP2 to this variant, so PP2 was not assessed.
PP3	Not met	Computational evidence is mixed and does not consistently support a damaging effect. REVEL was 0.507 and BayesDel was 0.164625, while SpliceAI predicted no significant splice impact with a maximum delta score of 0.05; taken together, these data do not support PP3.	revel bayesdel spliceai
PP4	Not assessed	No phenotype information for an affected individual carrying this variant was provided, so PP4 was not assessed.
PP5	N/A	Assertion-only criteria were not applied. ClinVar contains a single submission classifying this variant as uncertain significance, which does not support PP5.	clinvar
BA1	Not met	This variant was absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is far below the benign BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant was absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency does not exceed the benign BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a context sufficient for BS2, so BS2 was not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study of this exact variant was identified showing normal function, so BS3 was not assessed.	oncokb
BS4	Not assessed	No family data were identified showing lack of segregation with disease, so BS4 was not assessed.
BP1	Not assessed	Available evidence does not provide a supported gene-level framework for applying BP1 to this missense variant, so BP1 was not assessed.
BP2	Not assessed	No evidence was identified that this variant occurs in cis with a pathogenic variant or in trans with a pathogenic variant in a fully explained dominant case, so BP2 was not assessed.
BP3	Not assessed	No evidence was identified that this variant lies in a repetitive region without known function, so BP3 was not assessed.
BP4	Not met	Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, but REVEL was 0.507 and BayesDel was 0.164625, so the available in silico evidence does not support BP4.	revel bayesdel spliceai
BP5	Not assessed	No case-specific phenotype data or alternative molecular diagnosis were provided, so BP5 was not assessed.
BP6	N/A	Assertion-only benign criteria were not applied. ClinVar does not contain a benign or likely benign submission for this variant, so BP6 is not applicable.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or intronic change at a position without predicted splice impact, so BP7 is not applicable.

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