Classification rationale

BP4 VUS

CTNNA1 c.1193A>G missense · exon 9

BP4 supporting: REVEL 0.079 meets the missense BP4 threshold of <=0.29.

BP4 → VUS

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.

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

CTNNA1 NM_001903.5

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 23 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met at supporting strength: missense REVEL score 0.079 meets the BP4 threshold of <=0.29.

The normalized consequence is missense, NP_001894.2:p.(Asn398Ser), so REVEL is the sole applicable PP3/BP4 path.REVEL score is 0.079, meeting the supplied ClinGen SVI BP4 supporting threshold <=0.29 (Pejaver et al. 2022, PMID:36413997).SpliceAI and BayesDel were not used for this missense BP4 assessment; BayesDel has no generic ACMG-strength calibration.

Assessed · not applied · 7 not met · 16 not assessed

Pathogenic

PS1 PS1 could not be assessed because its agent did not produce valid output.

PS2 Not assessed: parental genotypes and confirmed maternity/paternity are not documented for a de novo CTNNA1 c.1193A>G observation.

PS3 Not assessed: no variant-specific validated functional assay or assay-control result for CTNNA1 p.Asn398Ser was identified.

PS4 Not assessed: no exact-variant case-control enrichment, odds ratio, or adequately documented affected-case series was identified.

PM1 PM1 could not be assessed because its agent did not produce valid output.

PM2 Not met: default all-comers AF is 0.000132166 in gnomAD v4.1, exceeding the 0.0001 PM2 threshold.

PM3 Not assessed: no affected-proband observation with a pathogenic variant and no phase information establishing trans or cis is reported.

PM5 PM5 could not be assessed because its agent did not produce valid output.

PM6 Not assessed: no variant-specific assumed de novo occurrence or family-history context is documented for CTNNA1 c.1193A>G.

PP1 Not assessed: no informative affected or unaffected relatives, meioses, or phenotype-concordant segregation data are reported for CTNNA1 c.1193A>G.

PP2 PP2 could not be assessed because its agent did not produce valid output.

PP3 Not met: missense REVEL score 0.079 is below the PP3 supporting threshold of 0.644.

PP4 Not assessed: no carrier phenotype or highly specific clinical diagnostic finding was supplied for this exact variant.

PP5 Not met: ClinVar has 0 expert-panel submissions for the exact variant, and available laboratory assertions are not qualifying Pathogenic/Likely pathogenic expert-panel evidence.

Benign

BA1 Not met: the highest gnomAD v4.1 subgroup frequency is 0.000467065, far below the 0.05 BA1 threshold.

BS1 Not met: the highest gnomAD v4.1 subgroup frequency is 0.000467065, below the generic 0.01 BS1 threshold.

BS2 Not met: gnomAD v2.1 and v4.1 report zero homozygotes, so the BS2 healthy-homozygote observation is absent.

BS3 Not assessed: no validated normal-function assay with appropriate controls for CTNNA1 p.Asn398Ser was identified.

BS4 Not assessed: no adequately tested affected relatives lacking CTNNA1 c.1193A>G are documented for non-segregation.

BP1 BP1 could not be assessed because its agent did not produce valid output.

BP2 Not assessed: no second pathogenic variant or cis/trans phase information is documented for this missense variant.

BP5 Not assessed: no affected case with a documented alternate molecular explanation was supplied for this exact variant.

BP6 Not met: ClinVar has 0 expert-panel submissions; the exact-variant Benign and Likely benign assertions are single-submitter laboratory records.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000132166; MAF= 0.01322%, 213/1611606 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000467065; MAF= 0.04671%, 35/74936 alleles, homozygotes = 0); grpmax FAF= 0.00034503.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000103222; MAF= 0.01032%, 29/280948 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000442336; MAF= 0.04423%, 11/24868 alleles, homozygotes = 0); grpmax FAF= 0.00022535.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.013% · 213 / 1,611,606
0 hom · FAF 0.035%

African/African American 35 / 74,936	0.047%
European (non-Finnish) 160 / 1,178,566	0.014%
East Asian 4 / 44,776	0.0089%
South Asian 7 / 90,644	0.0077%
Admixed American 3 / 59,716	0.005%
Ashkenazi Jewish 1 / 29,578	0.0034%
Remaining individuals 2 / 62,394	0.0032%
European (Finnish) 1 / 64,034	0.0016%

+ 2 not observed (Amish, Middle Eastern)

gnomAD v2.1

0.01% · 29 / 280,948
0 hom · FAF 0.023%

African/African American 11 / 24,868	0.044%
European (non-Finnish) 13 / 128,676	0.01%
European (Finnish) 2 / 25,090	0.008%
Admixed American 2 / 34,782	0.0058%
East Asian 1 / 19,848	0.005%

+ 3 not observed (Ashkenazi Jewish, Remaining individuals, South Asian)

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 (5 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 657823)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.079. BayesDel score = -0.51631.

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 not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

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.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

22388873 ↗ Familial gastric cancer: guidelines for diagnosis, treatment and periodic surveillance. CLINVAR

27153395 ↗ Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. CLINVAR

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

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. CLINVAR

20301318 ↗ Diffuse Gastric and Lobular Breast Cancer Syndrome. CLINVAR

26324357 ↗ American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. CLINVAR

Check your email

Reset your password

Enter an access code

Your allowance