LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-28
Case ID: NM_001904.4_c.134C_T_20261028_111532
Framework: ACMG/AMP 2015
Variant classification summary

NM_001904.4:c.134C>T

CTNNB1  · NP_001895.1:p.(Ser45Phe)  · NM_001904.4
GRCh37: chr3:41266137 C>T  ·  GRCh38: chr3:41224646 C>T
Gene: CTNNB1 Transcript: NM_001904.4
Final call
Likely Pathogenic
PS1 strong PS3 supporting PM1 moderate PM2 supporting BP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
CTNNB1
Transcript
NM_001904.4
Protein
NP_001895.1:p.(Ser45Phe)
gnomAD AF
ClinVar
other
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS1 strong: CTNNB1 p.Ser45Phe is repeatedly reported and shows activating functional effects.
2
PS3 supporting: p.Ser45Phe increased beta-catenin target-gene expression and reporter activity in variant-specific assays.
3
PM1 moderate: residue Ser45 is in a recurrent CTNNB1 exon 3 degron hotspot.
4
PM2 supporting: the exact variant is absent from gnomAD v2.1 and v4.1.
5
BP1 supporting: most reported CTNNB1 syndrome pathogenic variants are truncating; BP1 alone does not meet a benign rule.
Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one moderate pathogenic criterion supports Likely Pathogenic; the additional supporting criteria do not create a benign rule.
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: CTNNB1 p.Ser45Phe is repeatedly reported and showed approximately 22-fold TOP-flash activation in a functional cancer study.
PMID:10435629 PMID:18282277 PMID:26686699 clinvar
PS2 Not assessed Not assessed: no documented affected proband, negative family history, and confirmed maternity plus paternity for this variant.
PS3 Met Met at supporting: p.Ser45Phe increased Axin2, Cyclin D1, and c-Myc expression 8.2-, 9.5-, and 4.9-fold in variant-bearing desmoid cells.
PMID:26686699 PMID:18282277
PS4 Not assessed Not assessed: affected-cohort reports lack an independent control frequency or OR/RR with 95% CI required to evaluate PS4 (>5.0 and CI excluding 1.0).
PMID:10435629 PMID:18282277 PMID:26686699 gnomad_v2 gnomad_v4
PM1 Met Met: residue S45 is in a statistically significant CTNNB1 hotspot, with recurrent mutations and altered beta-catenin stability/function reported.
PMID:30699286 PMID:18282277
PM2 Met Met at supporting strength: the variant was absent from gnomAD v2.1 and v4.1, giving an observed frequency of 0 versus the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no inheritance or phase data establish a recessive disorder or show this variant in trans with a pathogenic allele.
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 verified different pathogenic missense substitution at CTNNB1 residue Ser45 was available for comparison.
pm5_candidates
PM6 Not assessed Not assessed: no affected germline proband or parental testing demonstrates an assumed de novo occurrence without maternity and paternity confirmation.
PP1 Not assessed Not assessed: no affected relatives, informative meioses, or familial genotype-phenotype co-segregation data are reported.
PP2 Not assessed Not assessed: CTNNB1 missense disease mechanism is documented, but no gene-level benign-missense-rate evidence was available.
gnomad_v2 gnomad_v4
PP3 Not met Not met: REVEL 0.353 is below the generic PP3 supporting threshold of 0.644 for this missense variant.
revel
PP4 Not assessed Not assessed: no patient phenotype or family history is available to determine whether it is highly specific for a single-gene disease.
PP5 Not met Not met: exact-variant ClinVar data show zero expert-panel submissions, so no qualifying pathogenic expert-panel classification supports PP5.
clinvar
BA1 Not met Not met: the variant was absent from gnomAD v2.1 and v4.1, far below the >=0.05 stand-alone benign-frequency threshold.
gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant was absent from gnomAD v2.1 and v4.1, providing no allele frequency above the disorder-expected frequency or the 1% default.
gnomad_v2 gnomad_v4
BS2 Not met Not met: no healthy-adult observation of the variant as a heterozygote, homozygote, or hemizygote was documented.
gnomad_v2 gnomad_v4
BS3 Not met Not met: variant-specific assays report increased beta-catenin signaling, including approximately 22-fold TOP-flash reporter activation rather than preserved function.
PMID:26686699 PMID:18282277
BS4 Not assessed Not assessed: no affected relatives have documented genotypes showing that the variant fails to segregate with disease.
BP1 Met Met: most reported CTNNB1 syndrome pathogenic variants are nonsense or frameshift changes generating premature termination codons.
pvs1_gene_context
BP2 Not assessed Not assessed: no affected-proband or family testing shows this variant in trans or cis with a pathogenic variant.
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: REVEL 0.353 exceeds the generic BP4 supporting threshold of 0.29 for this missense variant.
revel
BP5 Not assessed Not assessed: no case-level alternate molecular basis for disease is documented alongside this variant.
BP6 Not met Not met: exact-variant ClinVar data show zero expert-panel submissions, so no qualifying benign expert-panel classification supports BP6.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
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.