Classification rationale

PM2 VUS

CTNNA1 c.1618C>T

The CTNNA1 c.1618C>T (p.Arg540Cys) variant has been reported in ClinVar, where it is currently classified as uncertain significance by 4 clinical laboratories without expert panel review.¹ This variant is rare in population databases, with gnomAD v2.1 showing 1/251442 alleles (0.00040%) and gnomAD v4.1 showing 11/1613994 alleles (0.00068%), both below the 0.1% PM2 threshold and with no homozygotes observed.² No variant-specific well-established functional study was identified for p.Arg540Cys in the retrieved materials.³ In silico evidence is not concordant enough to support either PP3 or BP4: SpliceAI predicts no splice impact (max delta score 0.00), while REVEL is 0.305 and BayesDel is 0.105968.⁴

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗PMID:32051609 ↗

4 spliceai ↗revelbayesdel

Gene diagram · NM_001903.5 · variants mapped to exon structure

CTNNA1 NM_001903.5

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 22 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is rare in population databases. In gnomAD v2.1 it is present at 1/251442 alleles (AF 0.00040%), and in gnomAD v4.1 at 11/1613994 alleles (AF 0.00068%), both well below the 0.1% PM2 threshold, with no homozygotes observed.

gnomAD v2.1 total AF 3.97706e-06AC 1/251442hom 0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No evidence was identified showing that this nucleotide change creates the same amino acid substitution as a previously established pathogenic variant.

PS2 No confirmed de novo occurrence data were identified for this variant.

PS3 No variant-specific well-established functional study was identified for p.Arg540Cys.

PS4 This variant is listed in ClinVar as uncertain significance by 4 clinical laboratories, but no case-control enrichment, prevalence data, or statistically increased occurrence in affected individuals were identified.

PM1 This variant was not identified in a statistically significant mutational hotspot, and no well-established critical functional domain enrichment evidence was identified for residue Arg540.

PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.

PM6 No assumed de novo occurrence data were identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish CTNNA1 as a gene in which missense variation is a common disease mechanism with a low rate of benign missense variation, so PP2 was not applied.

PP3 Available computational evidence does not provide consistent support for a damaging effect.

PP4 No phenotype data specific enough to support a highly CTNNA1-specific clinical presentation were identified for this variant.

PP5 No reputable source classification supporting pathogenicity beyond single-submitter uncertain-significance assertions was identified for this variant.

Benign

BA1 Population frequency is far below the standalone benign threshold.

BS1 Population frequency does not exceed the benign strong threshold.

BS2 This variant has not been observed in homozygous state in gnomAD, so the available population data do not support observation in healthy individuals sufficient for BS2.

BS3 No well-established functional study showing a normal or benign effect for p.Arg540Cys was identified.

BS4 No data were identified showing lack of segregation of this variant with disease in a family.

BP1 Although CTNNA1 loss of function is an established disease mechanism, the available materials do not support using BP1 to treat missense variation in this gene as generally benign.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2.

BP4 Available computational evidence does not provide consistent support for a benign effect.

BP5 No alternate molecular explanation was identified that would clearly account for the phenotype independently of this variant.

BP6 No reputable source classified this variant as benign or likely benign.

N/A · 5 PVS1 · 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= 6.81539e-06; MAF= 0.00068%, 11/1613994 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.00117e-05; MAF= 0.00500%, 3/59986 alleles, homozygotes = 0); grpmax FAF= 1.327e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.97706e-06; MAF= 0.00040%, 1/251442 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89184e-05; MAF= 0.00289%, 1/34580 alleles, homozygotes = 0).

🇨🇦 CA

This variant is absent from gnomAD-Canada.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00068% · 11 / 1,613,994
0 hom · FAF 0.0013%

Admixed American 3 / 59,986	0.005%
European (non-Finnish) 8 / 1,180,052	0.00068%

+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,442
0 hom

Admixed American

1 / 34,580

0.0029%

+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 661855)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.305. BayesDel score = 0.105968.

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. CTNNA1, a cytoplasmic adhesion protein, is infrequently altered in cancer.

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; COSV100242785, n = 4 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

Triaged references · 4 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

32051609 ↗ Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?