NM_001098209.2:c.110C>T

CTNNB1 · NP_001091679.1:p.(Ser37Phe) · NM_001098209.2

GRCh37: chr3:41266113 C>T · GRCh38: chr3:41224622 C>T

Gene: CTNNB1 Transcript: NM_001098209.2

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 moderate

Variant details

Gene

CTNNB1

Transcript

NM_001098209.2

Protein

NP_001091679.1:p.(Ser37Phe)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001098209.2:c.110C>T (p.Ser37Phe) in CTNNB1 is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at moderate strength.

Ser37 is a critical phosphorylation residue within the N-terminal β-TRCP degron motif (DpSGXXpS, residues 32-37), a well-characterized functional domain mediating β-catenin ubiquitination and degradation. This position is a statistically significant cancer mutational hotspot, meeting PM1 at moderate strength.

Saturation genome editing across all 342 possible missense substitutions in the CTNNB1 exon 3 degron (positions 31-48) demonstrated that p.Ser37Phe confers gain-of-function Wnt pathway activation (PMID:41629672). Independently, direct functional testing of β-catenin S37F in melanoma cell lines confirmed constitutive TCF/LEF transcriptional activity, IL-10 induction, and immune suppression (PMID:22815287). Two or more independent publications with systematic functional characterization meet PS3 at strong strength.

Combined classification: PS3 (strong) + PM1 (moderate) + PM2 (moderate) = Likely Pathogenic per generic ACMG/AMP 2015 combination rules (1 strong + 2 moderate).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	NM_001098209.2:c.110C>T (p.Ser37Phe) is a missense variant and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	The only single-nucleotide substitution producing p.Ser37Phe from the TCT codon is c.110C>T, which is the query variant itself. No alternative nucleotide change yielding the same amino acid change has been established as pathogenic, so a comparator for PS1 does not exist.
PS2	Not met	No de novo occurrence report for this variant was identified in the reviewed literature.
PS3	Met	Saturation genome editing (PMID:41629672) systematically characterized all 342 possible missense mutations in the CTNNB1 exon 3 degron hotspot (positions 31–48), directly including p.Ser37Phe, and demonstrated gain-of-function signaling activation via an endogenous-locus reporter assay. Independently, PMID:22815287 directly tested the β-catenin S37F variant in luciferase reporter assays, chromatin immunoprecipitation, and IL-10 induction experiments in human melanoma cell lines, confirming constitutive Wnt pathway activation. PMID:10192393 independently identified S37F as a β-catenin-stabilizing mutation in pilomatricomas. Two or more independent publications provide systematic functional evidence supporting a gain-of-function pathogenic effect for this variant.	PMID:41629672 PMID:22815287 PMID:10192393
PS4	Not met	No case-control or prevalence data comparing affected vs. unaffected individuals was identified. The literature_pass indexed PMIDs 23788249 and 25356965 for PS4, but these are ACMG policy statements, not patient cohort studies.
PS5	Not met	No independent reputable source with transparent evidence has classified this variant as pathogenic. The ClinVar OMIM submission (SCV000039439) lacks assertion criteria and is derived from a single literature-only review of somatic pilomatricoma data.
PM1	Met	Ser37 is a critical GSK3β phosphorylation residue within the N-terminal β-TRCP degron motif (DpSGXXpS, residues 32–37). This well-characterized functional domain mediates phosphorylation-dependent ubiquitination and degradation of β-catenin. Saturation mutagenesis (PMID:41629672) confirms this position is essential for degron function, and the variant lies within a statistically significant cancer mutational hotspot (cancerhotspots.org). Missense variants in this domain are a recognized gain-of-function mechanism.	PMID:41629672 PMID:10192393
PM2	Met	The variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0). This meets the non-VCEP PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	Automated PM5 candidate harvesting (pm5_candidates.json) returned zero same-residue comparator variants. Although S37C (TCT→TGT) was identified as a somatic activating mutation in pilomatricomas (PMID:10192393), it has not been established as a pathogenic germline variant through ClinVar or other curated databases with sufficient evidence to serve as a PM5 comparator for germline classification.
PM6	Not met	No de novo occurrence report for this variant was identified in the reviewed literature.
PP1	Not met	No segregation data or family studies were identified in the reviewed literature.
PP2	Not met	CTNNB1 germline disease (CTNNB1 syndrome, MIM 615075) is primarily caused by loss-of-function variants (nonsense, frameshift). The p.Ser37Phe variant is a gain-of-function missense change not characteristic of the LoF disease mechanism. PP2 (missense variants are a common mechanism of disease with low rate of benign missense variation) does not apply in this context.
PP3	Not met	Computational evidence is equivocal and does not reach consensus support for a deleterious effect. REVEL score is 0.586 (borderline, below the typical 0.7 damaging threshold). BayesDel score is 0.143 (low, predicted benign). SpliceAI max delta score is 0.00 (no splicing impact). Only one of three predictors is borderline, and in silico tools are not optimized for gain-of-function mechanisms such as the β-catenin stabilization caused by S37F.	revel bayesdel spliceai
PP4	Not met	No specific patient phenotype or clinical data were provided for this case to assess whether the variant's phenotype is highly specific for a disease.
PP5	Not met	The ClinVar classification is 'Pathogenic' from OMIM (SCV000039439) with 'no assertion criteria provided' and somatic disease context (pilomatricoma). This does not constitute a reputable source with transparent evidence suitable for PP5 application in germline classification.
BA1	Not met	Variant is absent from gnomAD (allele frequency = 0), well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from gnomAD (allele frequency = 0), well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in healthy adults has been documented. The variant is absent from gnomAD and no unaffected carriers have been reported.
BS3	Not met	Functional evidence from saturation mutagenesis (PMID:41629672) and direct testing (PMID:22815287) demonstrates gain-of-function — constitutive Wnt pathway activation — rather than a benign or normal functional effect. No evidence supports that the variant does not alter protein function.	PMID:41629672 PMID:22815287
BS4	Not met	No cosegregation data in affected families is available to assess lack of segregation with disease.
BP1	Not met	Although CTNNB1 syndrome (MIM 615075) is primarily caused by loss-of-function truncating variants, p.Ser37Phe is a well-characterized gain-of-function missense variant with a distinct functional mechanism (β-catenin stabilization) rather than a variant of uncertain significance. BP1 does not apply when the missense variant has an established alternative pathogenic mechanism.	PMID:41629672 PMID:22815287
BP2	Not met	No observation in trans with a pathogenic variant has been reported.
BP3	N/A	SKIP: trivially not applicable (in-frame indel criteria).
BP4	Not met	Computational evidence is equivocal and does not provide multiple consistent lines supporting no impact. While BayesDel (0.143) and SpliceAI (0.00) suggest benign/no impact, REVEL (0.586) is borderline. The lack of consensus and the known gain-of-function mechanism (not captured by these tools) preclude application of BP4.	revel bayesdel spliceai
BP5	Not met	No alternative molecular cause for the disease has been identified in this case to support BP5.
BP6	N/A	BP6 applies to synonymous variants with no predicted splice impact. This is a missense variant.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a missense variant.

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