Variant classification summary

NM_001904.4:c.121A>G

CTNNB1 · NP_001895.1:p.(Thr41Ala) · NM_001904.4

GRCh37: chr3:41266124 A>G · GRCh38: chr3:41224633 A>G

Gene: CTNNB1 Transcript: NM_001904.4

Final call

Likely Pathogenic

PS1 strong PS3 supporting PM2 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Thr41Ala)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: identical p.Thr41Ala was reported in multiple tumor studies and functionally activated beta-catenin signaling.

2

Likely Pathogenic: a triplicate TOP-FLASH assay showed increased beta-catenin activation for T41A.

3

Likely Pathogenic: the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus two supporting pathogenic criteria yields Likely Pathogenic.

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	Met	Met: the identical CTNNB1 p.Thr41Ala change was reported in three tumor studies and activated beta-catenin signaling in a reporter assay.	PMID:16140927 PMID:18419788 PMID:10435629 PMID:24735922
PS2	Not assessed	Not assessed: no proband-parent genotypes, confirmed maternity and paternity, phenotype-confirmed disease status, or documented absence of family history are available.
PS3	Met	Met at supporting strength: triplicate TOP-FLASH assays showed CTNNB1 T41A activated beta-catenin more strongly than K335I and N387K in Huh7 cells.	PMID:24735922
PS4	Not met	Not met: exact p.T41A tumor reports lack unaffected or population control counts, so no qualifying OR/95% CI comparison exceeds the PS4 threshold.	PMID:16140927 PMID:18419788 PMID:10435629 PMID:24735922 gnomad_v2 gnomad_v4
PM1	Not assessed	Not assessed: Thr41 is a recurrent functional oncogenic codon, but no evidence establishes absence of benign variation across the relevant region.	PMID:12799363 PMID:10435629 PMID:24735922 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the supplied PM2 <=0.0001 population-frequency default.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: CTNNB1-related neurodevelopmental disorder is autosomal dominant, whereas PM3 applies only to recessive disorders with a pathogenic variant confirmed in trans.
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 met	Not met: no different pathogenic missense substitution at CTNNB1 residue Thr41 was identified; the reported comparator was the same T41A change.	PMID:16140927 PMID:18419788 PMID:10435629 PMID:24735922 pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo occurrence or parental testing is documented, and somatic tumor reports do not establish germline de novo status.
PP1	Not assessed	Not assessed: no affected relatives, familial variant testing, co-segregation results, or informative meioses are reported for this variant.
PP2	Not assessed	Not assessed: no validated CTNNB1 benign-missense rate and common missense disease mechanism are established for the relevant disease context.
PP3	Not met	Not met: missense REVEL score 0.403 is below the >= 0.644 threshold for supporting PP3.	revel
PP4	Not assessed	Not assessed: no sufficiently specific patient phenotype or family history is available to establish a single genetic etiology for p.T41A.	PMID:16140927 PMID:18419788 PMID:10435629
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification; the audit reports zero expert-panel submissions.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the >=0.05 allele-frequency threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, with no grpmax FAF at or above the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no healthy adult individual is reported carrying the variant in the heterozygous, homozygous, or hemizygous state.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no benign functional assay was identified, while the available T41A reporter assay showed increased beta-catenin activation.	PMID:24735922
BS4	Not assessed	Not assessed: no affected-family-member genotypes or phenotypes are available to demonstrate lack of segregation or exclude phenocopies.
BP1	Not assessed	Not assessed: the bundle lacks a citable disease-specific demonstration that CTNNB1 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no germline family or affected-proband observation establishes p.T41A in trans or cis with a pathogenic variant, and the available reports are somatic tumor studies.	PMID:16140927 PMID:18419788 PMID:10435629 PMID:24735922
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 0.403 exceeds the <= 0.29 supporting BP4 cutoff.	revel
BP5	Not assessed	Not assessed: tumor somatic-status testing does not show that an alternate molecular basis explains disease in a case carrying p.T41A.	PMID:16140927 PMID:18419788 PMID:10435629
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification, and the audit reports zero expert-panel submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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