NM_001098209.2:c.674G>A

CTNNB1 · NP_001091679.1:p.(Arg225His) · NM_001098209.2

GRCh37: chr3:41267003 G>A · GRCh38: chr3:41225512 G>A

Gene: CTNNB1 Transcript: NM_001098209.2

Final call

VUS

PM2 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001098209.2

Protein

NP_001091679.1:p.(Arg225His)

gnomAD AF

1.8586784796010036e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001098209.2:c.674G>A (p.Arg225His) is a missense variant in CTNNB1, present at extremely low frequency in population databases (gnomAD v2.1 AF=3.98e-06, v4.1 AF=1.86e-06), satisfying PM2 at supporting strength.

This variant is classified as Uncertain Significance in ClinVar (ID 3257135) by two clinical laboratories with 1-star review status. It has been observed in COSMIC (n=4) in somatic cancers but lacks variant-specific functional characterization.

Computational predictors do not support a deleterious effect: REVEL score 0.402, BayesDel -0.008, SpliceAI max delta 0.10. No functional studies, segregation data, or de novo reports are available for this variant.

Only one criterion is met (PM2 at supporting strength). No pathogenic or benign criteria are satisfied. In accordance with ACMG/AMP 2015 combination rules, a single supporting pathogenic criterion with no opposing benign criteria results in a classification of Uncertain Significance.

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	PVS1 is not applicable: NM_001098209.2:c.674G>A is a missense variant (p.Arg225His). The ClinGen SVI PVS1 framework (PMC6185798) limits PVS1 to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This variant falls into the 'other' bucket and does not qualify.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No known pathogenic variant with the same amino acid change (p.Arg225His) at this position has been established in ClinVar or the literature. This variant is classified as VUS by two clinical laboratories.	clinvar pm5_candidates
PS2	Not met	No de novo occurrence reports were identified for this variant in the available literature or ClinVar submissions.	clinvar
PS3	Not met	No variant-specific functional studies were identified. OncoKB reports unknown oncogenic effect with no curated functional evidence. No publications with experimental functional characterization of p.Arg225His were found.	oncokb
PS4	Not met	No case-control studies or statistically significant enrichment of this variant in affected individuals versus controls has been reported.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	No established pathogenic variant with the same amino acid change at this position has been identified in ClinVar or the literature. The residue Arg225 has no pathogenic missense comparators.	clinvar pm5_candidates
PM1	Not met	Residue Arg225 is not located in a statistically significant mutational hotspot per cancerhotspots.org. While codon 225 lies within the armadillo repeat domain of β-catenin, the canonical CTNNB1 hotspots are at N-terminal phosphorylation sites (codons 33, 37, 41, 45). Domain-level PM1 application without residue-specific hotspot data is not supported in the generic ACMG framework.
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-06 (1/251,024 alleles), gnomAD v4.1 AF=1.86e-06 (3/1,614,050 alleles), gnomAD v4.1 grpmax FAF=6.8e-07. All observed frequencies are well below the 0.1% PM2 threshold. No homozygotes reported.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense comparator variants at the same amino acid residue (Arg225) were identified. Automated PM5 candidate harvesting returned zero candidates.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence of this variant has been reported in the available literature or ClinVar submissions. PM6 requires a de novo observation (with or without confirmed parentage).	clinvar
PP1	Not met	No co-segregation data in affected families is available for this variant.
PP2	Not met	While CTNNB1 is associated with autosomal dominant neurodevelopmental disorder (CTNNB1 syndrome, MIM 615075) and loss-of-function is an established disease mechanism, PP2 requires demonstration of a low rate of benign missense variation in the gene (e.g., high missense Z-score). Missense constraint metrics were not available for this assessment. Furthermore, pathogenic missense variants are a recognized disease mechanism in CTNNB1 alongside truncating variants.	pvs1_gene_context
PP3	Not met	In silico computational predictors do not support a deleterious effect: REVEL score 0.402 (below typical pathogenic threshold of 0.5), BayesDel score -0.008 (in benign range, below 0), and SpliceAI max delta score 0.10 (no predicted splicing impact, below 0.2 threshold). All three predictors converge on a neutral or benign interpretation.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data were provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classifies this variant as Uncertain Significance (ClinVar ID 3257135) with review status 'criteria provided, single submitter' (1-star). PP5 requires a reputable source with pathogenic classification, and per framework rules ClinVar 3-star expert panel classification is required for supporting-level PP5 application.	clinvar
BA1	Not met	The maximum population allele frequency is 8.81e-06 in gnomAD v2.1 NFE, far below the BA1 threshold of >1%. This variant is not common in any population.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum population allele frequency is 8.81e-06 in gnomAD v2.1 NFE, far below the BS1 threshold of >0.3%. This variant is not observed at a frequency consistent with a benign polymorphism.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations in gnomAD (0 homozygotes in v2.1 and v4.1). No evidence of this variant occurring in trans with a pathogenic CTNNB1 variant in healthy individuals. Insufficient data to support BS2.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating a neutral or benign effect for p.Arg225His were identified. OncoKB reports unknown oncogenic effect with no curated functional evidence.	oncokb
BS4	Not met	No segregation data in affected families is available. BS4 requires non-segregation with disease in affected family members.
BP1	Not met	While the majority of CTNNB1 syndrome cases are caused by truncating variants, pathogenic missense variants in CTNNB1 are a recognized disease mechanism (PMID:33350591, PMID:36083290). BP1 requires that the gene is known to cause disease exclusively or primarily through truncating variants, which is not satisfied when missense variants are an established alternative mechanism.	pvs1_gene_context
BP2	Not met	No evidence of this variant occurring in trans with a pathogenic CTNNB1 variant in any individual. BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic recessive variant.
BP4	Not met	In silico predictors do not provide strong convergent evidence for a benign effect. While BayesDel (-0.008) and SpliceAI (max delta 0.10) are in benign range, REVEL score 0.402 is ambiguous and does not confidently predict benign impact. BP4 requires multiple lines of computational evidence strongly suggesting no impact.	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in this case. BP5 requires the variant to be found in a case with an established alternate molecular cause for the phenotype.
BP6	Not met	ClinVar classifies this variant as Uncertain Significance, not benign. BP6 requires a reputable source to classify the variant as benign. ClinVar ID 3257135 has 1-star review status ('criteria provided, single submitter') and a VUS classification.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_001098209.2:c.674G>A is a missense variant (p.Arg225His), not synonymous.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a single nucleotide substitution, not an in-frame indel.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CTNNB1-related disorders follow an autosomal dominant inheritance pattern; no recessive disease association is established.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a missense substitution with no protein length alteration.

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