Classification rationale

PM2 VUS

CTNNB1 c.269G>A

NM_001904.4:c.269G>A (p.Arg90Gln) is at extremely low frequency in population databases: absent from gnomAD v2.1 and gnomAD-Canada with 1 allele out of 1,613,962 in gnomAD v4.1 (AF 0.000062%), meeting PM2 at moderate strength.¹ This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (VariationID 1378784).² In silico predictors are equivocal (REVEL 0.455, BayesDel 0.221, SpliceAI delta 0.0) and do not meet thresholds for PP3 or BP4.³ This variant has been observed in somatic cancers (COSMIC COSV62707932, n = 2); no germline functional evidence is available.⁴ No de novo, segregation, case-control, or functional data are available for this variant. Multiple criteria remain unassessed.

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 clinvar ↗

3 revelbayesdelspliceai ↗

4 oncokb ↗

Gene diagram · NM_001904.4 · variants mapped to exon structure

CTNNB1 NM_001904.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 21 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

NM_001904.4:c.269G>A is at extremely low frequency in population databases: absent from gnomAD v2.1 and gnomAD-Canada; 1 allele out of 1,613,962 in gnomAD v4.1 (AF = 6.2e-7, 0.000062%), well below the 0.1% PM2 threshold. No homozygotes observed.

gnomAD v2.1: absent.gnomAD v4.1: 1/1613

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No established pathogenic missense variant at the same amino acid residue (Arg90) is available for comparison.

PS2 No de novo observation with confirmed maternity and paternity is available for this variant.

PS3 No well-established in vitro or in vivo functional studies demonstrate a damaging effect of NM_001904.4:c.269G>A (p.Arg90Gln).

PS4 Prevalence in affected individuals versus controls has not been established.

PM1 This variant does not lie in a statistically significant mutational hotspot.

PM6 No de novo observation (without confirmation of maternity/paternity) is available for this variant.

PP1 No co-segregation data with disease in multiple affected family members is available.

PP2 Insufficient data to assess whether CTNNB1 has a low rate of benign missense variation (e.g., gnomAD missense Z-score or constraint metric not available in this case).

PP3 In silico predictors do not reach damaging thresholds: REVEL score 0.455 is below the 0.5 threshold, BayesDel score 0.221 is below the 0.27 threshold, and SpliceAI predicts no splice impact (max delta = 0.0).

PP4 No patient phenotype or family history data are available to assess phenotypic specificity for CTNNB1 syndrome.

PP5 No reputable source has classified this variant as pathogenic.

Benign

BA1 Allele frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below the 1% BA1 threshold.

BS1 Allele frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below the 0.3% BS1 threshold.

BS2 No data available regarding observation of this variant in healthy adults where full penetrance of CTNNB1 syndrome would be expected at an early age.

BS3 No well-established functional studies demonstrate no damaging effect of this variant.

BS4 No non-segregation data with disease phenotype in multiple affected family members is available.

BP1 BP1 applies when primarily truncating variants cause disease in a gene.

BP2 No data available regarding observation in trans with a known pathogenic CTNNB1 variant.

BP4 Multiple lines of computational evidence do not consistently suggest no impact on the gene product.

BP5 No data available regarding a case with an alternative molecular cause for disease.

BP6 No reputable source has classified this variant as benign.

N/A · 6 PVS1 · PM3 · PM4 · PM5 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19593e-07; MAF= 0.00006%, 1/1613962 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47502e-07; MAF= 0.00008%, 1/1179938 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,962
0 hom

European (non-Finnish)

1 / 1,179,938

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1378784)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = 0.220613.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62707932, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?