NM_001904.4:c.134C>A

CTNNB1 · NP_001895.1:p.(Ser45Tyr) · NM_001904.4

GRCh37: chr3:41266137 C>A · GRCh38: chr3:41224646 C>A

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM1 moderate PM2 moderate

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Ser45Tyr)

gnomAD AF

ClinVar

Tier I - Strong

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PM1 (Moderate): Ser45 is a conserved phospho-residue of the beta-catenin destruction-complex degron, a hotspot lacking benign variation.

PM2 (Moderate): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.

With only PM1 and PM2 (both moderate) met, no Pathogenic or Benign ACMG/AMP combination is reached, so the variant is classified as Variant of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback rules require combinations such as (1 PVS1 + 1 PM), (1 PS + 1 PM), (3 PM), or higher; 2 moderate criteria (PM1 + PM2) alone do not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign threshold, so the variant defaults to 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	Not applicable: this is a missense substitution, not a null variant expected to trigger nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no independently classified pathogenic variant producing p.(Ser45Tyr) via another nucleotide change was found.
PS2	Not assessed	Not assessed: no proband phenotype or parental testing data were provided to evaluate a confirmed de novo occurrence.	clinvar final_classification_framework
PS3	Not assessed	Not assessed: the saturation genome editing screen reports only residue-level effects, not a result specific to p.Ser45Tyr.
PS4	Not assessed	Not assessed: no case-control comparison or enrichment analysis for this exact variant was available.
PM1	Met	Met (Moderate): Ser45 is a conserved phospho-residue of the beta-catenin degron, a functional hotspot lacking benign variation.	oncokb PMID:11955436 PMID:12000790 PMID:41629672
PM2	Met	Met (Moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected individual with a second pathogenic allele or phase data was documented.	clinvar
PM4	N/A	Not applicable: this is a missense substitution, so no change in protein length occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no independently classified pathogenic substitution at Ser45 was available as a comparator.	pm5_candidates
PM6	Not assessed	Not assessed: no reported de novo occurrence or parental genotypes were available.	clinvar final_classification_framework
PP1	Not assessed	Not assessed: no pedigree or family genotype data were provided to evaluate co-segregation.	clinvar final_classification_framework
PP2	N/A	Not applicable: germline CTNNB1 disease is driven by loss-of-function variants rather than missense enrichment.	pvs1_gene_context
PP3	Not met	Not met: REVEL 0.353 falls below the calibrated >=0.644 PP3 threshold.	spliceai revel bayesdel
PP4	Not assessed	Not assessed: no phenotype or diagnostic workup evidence specific to a CTNNB1-related germline disorder was available.	clinvar
PP5	Not assessed	Not assessed: the ClinVar record has no expert-panel assertion, only a somatic laboratory submission.	clinvar
BA1	Not met	Not met: absent from gnomAD, so population frequency is far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD, with no population frequency exceeding that expected for a CTNNB1-associated disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no unaffected adult carrier or homozygote observations with phenotype and age data were supplied.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay result for p.Ser45Tyr showing normal function was available.
BS4	Not assessed	Not assessed: no unaffected carriers or other informative non-segregation observations were provided.	clinvar final_classification_framework
BP1	Not met	Not met: despite loss-of-function being the germline disease mechanism, Ser45 is a documented oncogenic hotspot with functional evidence of missense pathogenicity.	oncokb PMID:11955436 PMID:12000790 PMID:41629672
BP2	Not assessed	Not assessed: no observation of the variant in cis or in trans with a pathogenic variant was documented.	clinvar
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.353 exceeds the calibrated <=0.290 BP4 threshold, in the indeterminate zone.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: no evidence of an alternative molecular diagnosis fully explaining the phenotype was available.
BP6	Not assessed	Not assessed: the ClinVar record has no expert-panel benign or likely benign assertion.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant as BP7 requires.	generic_acmg_combination_rules

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.