About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.674G>A, p.(Arg225His)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-06 (1/251,024 alleles), gnomAD v4.1 AF=1.86e-06 (3/1,614,050 alleles), gnomAD v4.1 grpmax FAF=6.8e-07. All observed frequencies are well below the 0.1% PM2 threshold. No homozygotes reported.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
3 / 1,614,050 alleles
gnomAD v4.1: 3 / 1,614,050 alleles. Recorded AF 1.85868e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98368e-06; MAF= 0.00040%, 1/251024 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81352e-06; MAF= 0.00088%, 1/113462 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.100 maximum delta
Recorded SpliceAI maximum delta score: 0.100. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV100846522, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 23 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001098209.2:c.674G>A (p.Arg225His) is a missense variant in CTNNB1, present at extremely low frequency in population databases (gnomAD v2.1 AF=3.98e-06, v4.1 AF=1.86e-06), satisfying PM2 at supporting strength.
This variant is classified as Uncertain Significance in ClinVar (ID 3257135) by two clinical laboratories with 1-star review status. It has been observed in COSMIC (n=4) in somatic cancers but lacks variant-specific functional characterization.
Computational predictors do not support a deleterious effect: REVEL score 0.402, BayesDel -0.008, SpliceAI max delta 0.10. No functional studies, segregation data, or de novo reports are available for this variant.
Only one criterion is met (PM2 at supporting strength). No pathogenic or benign criteria are satisfied. In accordance with ACMG/AMP 2015 combination rules, a single supporting pathogenic criterion with no opposing benign criteria results in a classification of Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-06 (1/251,024 alleles), gnomAD v4.1 AF=1.86e-06 (3/1,614,050 alleles), gnomAD v4.1 grpmax FAF=6.8e-07. All observed frequencies are well below the 0.1% PM2 threshold. No homozygotes reported. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/251
- 024 (AF=3.98e-06)
- NFE AF=8.81e-06
- gnomAD v4.1: 3/1
- 614
- 050 (AF=1.86e-06)
- grpmax FAF=6.8e-07
- gnomAD-Canada: absent.
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No known pathogenic variant with the same amino acid change (p.Arg225His) at this position has been established in ClinVar or the literature. This variant is classified as VUS by two clinical laboratories. Details ▾Hide ▴
Evidence considered
- ClinVar VUS classification (ID 3257135)
- no pathogenic comparator at same residue with same amino acid change identified.
Still missing
- No established pathogenic variant at Arg225 to serve as PS1 comparator.
Sources
clinvar ↗pm5_candidates
PS2 No de novo occurrence reports were identified for this variant in the available literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No de novo observations reported in ClinVar or the literature for NM_001098209.2:c.674G>A.
Still missing
- No parental testing or de novo confirmation data available.
Sources
PS3 No variant-specific functional studies were identified. OncoKB reports unknown oncogenic effect with no curated functional evidence. No publications with experimental functional characterization of p.Arg225His were found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
- COSMIC: observed n=4 in somatic cancers but no functional characterization.
Still missing
- No functional assay data for p.Arg225His
- no systematic range characterization encompassing residue 225.
Sources
PS4 No case-control studies or statistically significant enrichment of this variant in affected individuals versus controls has been reported. Details ▾Hide ▴
Evidence considered
- Variant is extremely rare in gnomAD (v2.1: 1/251
- 024
- v4.1: 3/1
- 614
- 050)
- no affected vs. control comparison data.
Still missing
- No case-control or prevalence data for this variant in disease cohorts.
Sources
PM1 Residue Arg225 is not located in a statistically significant mutational hotspot per cancerhotspots.org. While codon 225 lies within the armadillo repeat domain of β-catenin, the canonical CTNNB1 hotspots are at N-terminal phosphorylation sites (codons 33, 37, 41, 45). Domain-level PM1 application without residue-specific hotspot data is not supported in the generic ACMG framework. Details ▾Hide ▴
Evidence considered
- Hotspots: residue not significant
- exact variant not listed
- Arg225 is in armadillo repeat domain but not a recognized mutational hotspot.
PM5 No pathogenic missense comparator variants at the same amino acid residue (Arg225) were identified. Automated PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- 0 expert panel P/LP candidates at residue 225.
Still missing
- No established pathogenic missense variant at Arg225 for PM5 comparison.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence of this variant has been reported in the available literature or ClinVar submissions. PM6 requires a de novo observation (with or without confirmed parentage). Details ▾Hide ▴
Evidence considered
- No de novo reports for NM_001098209.2:c.674G>A in ClinVar or literature.
Still missing
- No de novo testing data available.
Sources
PP1 No co-segregation data in affected families is available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified.
Still missing
- No co-segregation analysis performed.
PP2 While CTNNB1 is associated with autosomal dominant neurodevelopmental disorder (CTNNB1 syndrome, MIM 615075) and loss-of-function is an established disease mechanism, PP2 requires demonstration of a low rate of benign missense variation in the gene (e.g., high missense Z-score). Missense constraint metrics were not available for this assessment. Furthermore, pathogenic missense variants are a recognized disease mechanism in CTNNB1 alongside truncating variants. Details ▾Hide ▴
Evidence considered
- CTNNB1 is a known disease gene for neurodevelopmental disorder
- primarily truncating mechanism but missense variants also reported as pathogenic (PMID:33350591
- PMID:36083290).
Still missing
- gnomAD missense constraint metrics (Z-score
- o/e) not available for formal PP2 evaluation.
Sources
pvs1_gene_context
PP3 In silico computational predictors do not support a deleterious effect: REVEL score 0.402 (below typical pathogenic threshold of 0.5), BayesDel score -0.008 (in benign range, below 0), and SpliceAI max delta score 0.10 (no predicted splicing impact, below 0.2 threshold). All three predictors converge on a neutral or benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.402 (ambiguous
- below 0.5)
- BayesDel: -0.008 (benign)
- SpliceAI max delta: 0.10 (no splicing impact).
Sources
PP4 No patient phenotype or clinical data were provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available for PP4 evaluation.
Still missing
- Patient phenotype and family history data not available.
PP5 ClinVar classifies this variant as Uncertain Significance (ClinVar ID 3257135) with review status 'criteria provided, single submitter' (1-star). PP5 requires a reputable source with pathogenic classification, and per framework rules ClinVar 3-star expert panel classification is required for supporting-level PP5 application. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- 2 clinical laboratories
- review status 'criteria provided
- single submitter' — not 3-star expert panel.
Sources
BA1 The maximum population allele frequency is 8.81e-06 in gnomAD v2.1 NFE, far below the BA1 threshold of >1%. This variant is not common in any population. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpop AF=8.81e-06 (NFE)
- gnomAD v4.1 max subpop AF=2.54e-06 (NFE)
- grpmax FAF=6.8e-07. All << 1%.
Sources
BS1 The maximum population allele frequency is 8.81e-06 in gnomAD v2.1 NFE, far below the BS1 threshold of >0.3%. This variant is not observed at a frequency consistent with a benign polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpop AF=8.81e-06 (NFE)
- gnomAD v4.1 max subpop AF=2.54e-06 (NFE). Both << 0.3%.
Sources
BS2 No homozygous observations in gnomAD (0 homozygotes in v2.1 and v4.1). No evidence of this variant occurring in trans with a pathogenic CTNNB1 variant in healthy individuals. Insufficient data to support BS2. Details ▾Hide ▴
Evidence considered
- gnomAD: 0 homozygotes in all datasets
- no observations in trans with pathogenic variants.
Still missing
- No data on occurrence in healthy adults homozygous or in trans.
Sources
BS3 No well-established functional studies demonstrating a neutral or benign effect for p.Arg225His were identified. OncoKB reports unknown oncogenic effect with no curated functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies showing no deleterious effect for p.Arg225His.
Still missing
- No functional characterization of p.Arg225His available.
Sources
BS4 No segregation data in affected families is available. BS4 requires non-segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data available.
Still missing
- No co-segregation analysis available.
BP1 While the majority of CTNNB1 syndrome cases are caused by truncating variants, pathogenic missense variants in CTNNB1 are a recognized disease mechanism (PMID:33350591, PMID:36083290). BP1 requires that the gene is known to cause disease exclusively or primarily through truncating variants, which is not satisfied when missense variants are an established alternative mechanism. Details ▾Hide ▴
Evidence considered
- CTNNB1 syndrome: primarily LOF mechanism but missense variants are documented as pathogenic (e.g.
- vitreoretinopathy phenotype
- PMID:33350591). BP1 does not apply when missense is a known disease mechanism.
Sources
pvs1_gene_context
BP2 No evidence of this variant occurring in trans with a pathogenic CTNNB1 variant in any individual. BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic recessive variant. Details ▾Hide ▴
Evidence considered
- No phase data available
- no reports of this variant in trans with a pathogenic CTNNB1 variant.
Still missing
- No phasing or trans configuration data.
BP4 In silico predictors do not provide strong convergent evidence for a benign effect. While BayesDel (-0.008) and SpliceAI (max delta 0.10) are in benign range, REVEL score 0.402 is ambiguous and does not confidently predict benign impact. BP4 requires multiple lines of computational evidence strongly suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.402 (ambiguous
- not strongly benign)
- BayesDel: -0.008 (benign range)
- SpliceAI: 0.10 (no splicing impact). Mixed signal
- insufficient for BP4.
Sources
BP5 No alternate molecular basis for disease has been identified in this case. BP5 requires the variant to be found in a case with an established alternate molecular cause for the phenotype. Details ▾Hide ▴
Evidence considered
- No alternate genetic diagnosis data available for this case.
Still missing
- No data on alternate molecular diagnosis in the proband.
BP6 ClinVar classifies this variant as Uncertain Significance, not benign. BP6 requires a reputable source to classify the variant as benign. ClinVar ID 3257135 has 1-star review status ('criteria provided, single submitter') and a VUS classification. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS (not benign)
- 1-star review status. Does not satisfy BP6.
Sources
PS5 No established pathogenic variant with the same amino acid change at this position has been identified in ClinVar or the literature. The residue Arg225 has no pathogenic missense comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned no same-residue pathogenic comparators
- ClinVar ID 3257135 is VUS.
Still missing
- No pathogenic variant at Arg225 established.
Sources
clinvar ↗pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_001098209.2:c.674G>A is a missense variant (p.Arg225His). The ClinGen SVI PVS1 framework (PMC6185798) limits PVS1 to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This variant falls into the 'other' bucket and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense substitution at c.674G>A
- predicted p.Arg225His
- not a null variant per ClinGen PVS1 decision tree.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CTNNB1-related disorders follow an autosomal dominant inheritance pattern; no recessive disease association is established. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a missense substitution with no protein length alteration. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This is a single nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001098209.2:c.674G>A is a missense variant (p.Arg225His), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous. BP7 does not apply.
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001098209.2
- Coding (HGVS c.)
- NM_001098209.2:c.674G>A
- Protein (HGVS p.)
- NP_001091679.1:p.(Arg225His)
- GRCh38
- chr3:41225512 G>A
- GRCh37
- chr3:41267003 G>A
- ClinVar
- 3257135
- COSMIC
- COSV100846522
Gene diagram
Every interpreted variant in CTNNB1, mapped onto the exon structure of NM_001098209.2. Select a row to find it on the plot.
CTNNB1NM_001098209.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CTNNB1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
3 / 1,614,050 alleles
AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
1 / 251,024 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,614,050 alleles · 0 hom · FAF 6.8e-07
| European (non-Finnish)3 / 1,179,996 | 2.5e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,024 alleles · 0 hom
| European (non-Finnish)1 / 113,462 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85868e-06; MAF= 0.00019%, 3/1614050 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54238e-06; MAF= 0.00025%, 3/1179996 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98368e-06; MAF= 0.00040%, 1/251024 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81352e-06; MAF= 0.00088%, 1/113462 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.402
- BayesDel
- -0.008
How the predictions were used
PP3 In silico computational predictors do not support a deleterious effect: REVEL score 0.402 (below typical pathogenic threshold of 0.5), BayesDel score -0.008 (in benign range, below 0), and SpliceAI max delta score 0.10 (no predicted splicing impact, below 0.2 threshold). All three predictors converge on a neutral or benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.402 (ambiguous
- below 0.5)
- BayesDel: -0.008 (benign)
- SpliceAI max delta: 0.10 (no splicing impact).
Sources
BP4 In silico predictors do not provide strong convergent evidence for a benign effect. While BayesDel (-0.008) and SpliceAI (max delta 0.10) are in benign range, REVEL score 0.402 is ambiguous and does not confidently predict benign impact. BP4 requires multiple lines of computational evidence strongly suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.402 (ambiguous
- not strongly benign)
- BayesDel: -0.008 (benign range)
- SpliceAI: 0.10 (no splicing impact). Mixed signal
- insufficient for BP4.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001098209.2:c.674G>A is a missense variant (p.Arg225His), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous. BP7 does not apply.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.402. BayesDel score = -0.00802185.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,614,050 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.100
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3257135/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41267003-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41225512-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-41225512-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001098209.2%3Ac.6…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/R225H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=223263620
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85868e-06; MAF= 0.00019%, 3/1614050 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54238e-06; MAF= 0.00025%, 3/1179996 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98368e-06; MAF= 0.00040%, 1/251024 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81352e-06; MAF= 0.00088%, 1/113462 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 3257135)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.402. BayesDel score = -0.00802185.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100846522, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.