Variant classification summary

NM_001904.4:c.1582C>T

CTNNB1 · NP_001895.1:p.(Arg528Cys) · NM_001904.4

GRCh37: chr3:41275687 C>T · GRCh38: chr3:41234196 C>T

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM2 supporting BP1 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Arg528Cys)

gnomAD AF

6.195756154864164e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 grpmax FAF is 8.75e-06, below the supporting threshold.

2

BP1 supporting: CTNNB1 disease evidence is predominantly associated with truncating or loss-of-function variants, although missense disease associations exist.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion plus one supporting benign criterion satisfies neither a benign nor a likely benign rule and does not satisfy any pathogenic rule, so the final call is VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no previously established pathogenic variant producing CTNNB1 p.Arg528Cys is documented in the available evidence.	clinvar PMID:28191889
PS2	Not assessed	Not assessed: parental maternity and paternity confirmation, proband disease status, and absence of family history are not documented.	PMID:28191889
PS3	Not assessed	Not assessed: no variant-specific, validated functional assay for CTNNB1 p.Arg528Cys was identified.	PMID:28191889 oncokb
PS4	Not assessed	Not assessed: no variant-specific affected-case and control counts were available to calculate the required OR/RR >5.0 with a confidence interval excluding 1.0.	PMID:28191889 gnomad_v4
PM1	Not assessed	Not assessed: CTNNB1 R528 has no documented significant hotspot or verified critical-domain evidence without benign variation.	hotspots cosmic
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 6.19576e-06 with grpmax FAF 8.75e-06, below the <=0.0001 PM2 threshold.	gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: PM3 is limited to recessive disorders, but this CTNNB1 case provides no recessive-disease context.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at CTNNB1 Arg528 is documented as pathogenic in the available evidence.	clinvar pm5_candidates PMID:28191889
PM6	Not assessed	Not assessed: no assumed de novo observation or parental genotype information is documented for the variant.	PMID:28191889
PP1	Not assessed	Not assessed: no affected relatives or informative cosegregation data are reported for the variant.	PMID:28191889
PP2	Not assessed	Not assessed: CTNNB1 evidence does not establish both low benign missense variation and a common missense disease mechanism.	pvs1_gene_context
PP3	Not met	Not met: missense REVEL score 0.4 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history specific enough for a single-gene disease was provided for this variant.	PMID:28191889
PP5	Not met	Not met: exact-match ClinVar is uncertain significance from a single laboratory, with no expert-panel pathogenic classification.	clinvar PMID:28191889
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 8.75e-06, below the 0.05 BA1 threshold, and the Amish point estimate uses only 910 alleles.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 8.75e-06, below the 0.01 BS1 default, while the Amish estimate is based on only 910 alleles.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but does not document a verified healthy adult genotype observation for BS2.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no variant-specific assay showed that CTNNB1 p.Arg528Cys has no damaging effect on protein function or splicing.	PMID:28191889 oncokb
BS4	Not assessed	Not assessed: no affected-relative genotypes or phenotypes are available to demonstrate lack of segregation.	PMID:28191889
BP1	Met	Met, supporting: most CTNNB1 syndrome patients in the cited evidence carry pathogenic nonsense or frameshift variants generating premature termination codons.	pvs1_gene_context
BP2	Not assessed	Not assessed: no pathogenic cis/trans partner or phase result is documented for p.Arg528Cys, so BP2 cannot be evaluated.	PMID:28191889
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.4 exceeds the BP4 supporting threshold of 0.29 and remains indeterminate.	revel
BP5	Not assessed	Not assessed: no documented carrier case had an independently established alternate molecular basis for disease.
BP6	Not met	Not met: exact-match ClinVar is uncertain significance, not benign or likely benign, and has no expert-panel classification.	clinvar PMID:28191889
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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