CTNNB1 c.876A>T, p.Lys292Asn
NM_001904.4:c.876A>T
Likely Pathogenic
The CTNNB1 K292N variant has strong functional evidence of a damaging effect (PS3), is located in a known mutational hotspot (PM1), is absent from population databases (PM2), and lacks computational support for benign impact (BP4). These data combine to support a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
CTNNB1
Transcript
NM_001904.4
MANE Select
Total Exons
15
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001904.3 | Alternative | 15 exons | Forward |
Variant Details
HGVS Notation
NM_001904.4:c.876A>T
Protein Change
K292N
Location
Exon 6
(Exon 6 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 292 in gene CTNNB1
Variant interpretation based on transcript NM_001904.4
Genome Browser
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HGVS InputNM_001904:c.876A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 292 in gene CTNNB1
Functional Summary
The CTNNB1 K292N variant has been functionally characterized as likely oncogenic, as it occurs at a statistically significant hotspot in various cancers, suggesting a damaging effect on the protein's function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
primateai: D
Benign:
CADD: 3.13metasvm: Tmetalr: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: NM_001904.4:c.876A>T (K292N) is a missense change, not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not introduce a null allele.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: no other pathogenic variant resulting in K292N has been reported. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no de novo data have been provided. Therefore, this criterion is not applied at Not Applied strength due to lack of de novo confirmation.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: functional studies have characterized CTNNB1 K292N as likely oncogenic at a statistically significant hotspot, demonstrating damaging effect on protein function. Therefore, this criterion is applied at Strong strength because robust in vitro/in vivo data support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case–control or prevalence data in disease cohorts vs controls. Therefore, this criterion is not applied at Not Applied strength due to absence of comparative prevalence data.
PM1
PM1 (Moderate)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: K292 lies at a statistically significant cancer hotspot in CTNNB1. Therefore, this criterion is applied at Moderate strength because the residue is within a known mutational hotspot.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: not observed in gnomAD, ExAC, 1000 Genomes or ESP. Therefore, this criterion is applied at Moderate strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: CTNNB1-related disease is dominant and no trans data are available. Therefore, this criterion is not applied at Not Applied strength because trans allele data are not relevant.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: K292N is a missense change without length alteration. Therefore, this criterion is not applied at Not Applied strength because there is no protein length change.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: no other pathogenic missense changes at residue K292 have been reported. Therefore, this criterion is not applied at Not Applied strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo assumptions have been made. Therefore, this criterion is not applied at Not Applied strength.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied at Not Applied strength.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: CTNNB1 disease mechanism is predominantly loss-of-function in germline contexts, not recurrent benign missense. Therefore, this criterion is not applied at Not Applied strength.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)'. The evidence for this variant shows: in silico predictions are mixed with a benign trend and SpliceAI shows no splicing impact. Therefore, this criterion is not applied at Not Applied strength due to lack of consistent deleterious computational support.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied at Not Applied strength.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at Not Applied strength.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at Not Applied strength.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: no reports in healthy individuals. Therefore, this criterion is not applied at Not Applied strength.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: functional studies indicate a damaging, oncogenic effect. Therefore, this criterion is not applied at Not Applied strength.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: CTNNB1 gain-of-function/missense mechanisms are known in cancer contexts. Therefore, this criterion is not applied at Not Applied strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no data on cis/trans configuration. Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: this is a missense substitution. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: mixed in silico predictions with an overall benign trend and no predicted splicing impact by SpliceAI. Therefore, this criterion is applied at Supporting strength because computational data do not support a damaging effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no alternate molecular diagnoses reported. Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no reputable benign reports exist. Therefore, this criterion is not applied at Not Applied strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: this is a non-synonymous change (missense). Therefore, this criterion is not applied at Not Applied strength.