About CTNNA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNA1 c.1618C>T, p.(Arg540Cys)
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 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.
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
11 / 1,613,994 alleles
gnomAD v4.1: 11 / 1,613,994 alleles. Recorded AF 6.81539e-06. Recorded homozygote count 0.
gnomAD 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).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions
4 Uncertain significance.
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. CTNNA1, a cytoplasmic adhesion protein, is infrequently altered in cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV100242785, 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.
28 criteria with recorded statuses: 1 met · 9 not met · 13 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
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.
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.
No variant-specific well-established functional study was identified for p.Arg540Cys in the retrieved materials.
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.
No criteria match.
Met · 1
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 3.97706e-06
- AC 1/251442
- hom 0.
- gnomAD v4.1 total AF 6.81539e-06
- AC 11/1613994
Still missing
- gnomAD-Canada lookup was unsuccessful.
Sources
Not met · 9 · evaluated, threshold not reached
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. Details ▾Hide ▴
Evidence considered
- ClinVar aggregate classification is uncertain significance with no expert panel review.
- No case-control enrichment evidence was identified in the retrieved materials.
Still missing
- Published case enrichment or case-control data would be needed.
Sources
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. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review found no hotspot row for CTNNA1 R540.
Still missing
- Gene-specific domain enrichment data would be needed to revisit PM1.
Sources
PP3 Available computational evidence does not provide consistent support for a damaging effect. SpliceAI predicts no meaningful splice impact (max delta score 0.00), REVEL is 0.305, and BayesDel is 0.105968; together these results do not reach a clear PP3 threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL 0.305.
- BayesDel 0.105968.
Still missing
- Additional validated gene-specific computational thresholds could refine this assessment.
Sources
PP5 No reputable source classification supporting pathogenicity beyond single-submitter uncertain-significance assertions was identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar shows only single-submitter uncertain significance classifications and no expert panel review.
Still missing
- An expert panel or other qualifying reputable pathogenic classification would be needed.
Sources
BA1 Population frequency is far below the standalone benign threshold. The highest observed gnomAD v4.1 overall frequency is 0.00068%, which is well below 1%. Details ▾Hide ▴
BS1 Population frequency does not exceed the benign strong threshold. The highest observed overall gnomAD frequency is 0.00068%, which is below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF 6.81539e-06.
- gnomAD v2.1 total AF 3.97706e-06.
Sources
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. Details ▾Hide ▴
Evidence considered
- No homozygotes in gnomAD v2.1 or v4.1.
Still missing
- Well-documented unaffected adult carriers in an appropriate disease context would be needed.
Sources
BP4 Available computational evidence does not provide consistent support for a benign effect. SpliceAI is neutral for splicing (max delta score 0.00), but REVEL 0.305 and BayesDel 0.105968 are not sufficiently benign to support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL 0.305.
- BayesDel 0.105968.
Still missing
- Additional validated gene-specific benign computational thresholds could refine this assessment.
Sources
BP6 No reputable source classified this variant as benign or likely benign. Available ClinVar submissions classify it as uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar aggregate classification is uncertain significance with no benign or likely benign assertion.
Still missing
- A qualifying benign or likely benign reputable-source assertion would be needed.
Sources
Not assessed · 13 · no assessment recorded
PS1 No evidence was identified showing that this nucleotide change creates the same amino acid substitution as a previously established pathogenic variant. Details ▾Hide ▴
Evidence considered
- ClinVar record review did not provide an established pathogenic same-amino-acid comparator.
Still missing
- A curated same-protein-change comparison set was not identified.
Sources
PS2 No confirmed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Evidence considered
- Available ClinVar summaries do not provide de novo evidence.
Still missing
- Parental testing or a published de novo case would be needed.
Sources
PS3 No variant-specific well-established functional study was identified for p.Arg540Cys. Available CTNNA1 literature in the retrieved materials focused on loss-of-function disease context rather than direct functional testing of this missense change. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
- Retrieved CTNNA1 paper addressed loss-of-function variants rather than this missense substitution.
Still missing
- A validated variant-specific functional assay would be needed.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Evidence considered
- Available records do not provide phase or recessive case data.
Still missing
- Phase data and a relevant recessive phenotype would be needed.
Sources
PM6 No assumed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Evidence considered
- Available records do not provide de novo evidence.
Still missing
- A reported de novo occurrence without full parental confirmation would be needed.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
- Retrieved materials did not report familial segregation for p.Arg540Cys.
Still missing
- Family segregation data would be needed.
Sources
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. Details ▾Hide ▴
Evidence considered
- Retrieved CTNNA1 materials emphasize loss-of-function disease mechanism rather than a clearly established missense-driven mechanism for PP2 use.
Still missing
- A validated gene-specific missense constraint and mechanism framework would be needed.
Sources
pvs1_gene_contextPMID:32051609 ↗
PP4 No phenotype data specific enough to support a highly CTNNA1-specific clinical presentation were identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar submissions did not provide phenotype detail sufficient for PP4.
Still missing
- Detailed phenotype and testing context would be needed.
Sources
BS3 No well-established functional study showing a normal or benign effect for p.Arg540Cys was identified. Details ▾Hide ▴
Evidence considered
- No variant-specific reviewed benign functional evidence was identified.
Still missing
- A validated benign functional assay would be needed.
Sources
BS4 No data were identified showing lack of segregation of this variant with disease in a family. Details ▾Hide ▴
Evidence considered
- Available records do not report segregation analyses.
Still missing
- Segregation studies demonstrating non-segregation would be needed.
Sources
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. Details ▾Hide ▴
Evidence considered
- CTNNA1 disease context in the reviewed materials centers on loss of function
- but a BP1-ready missense framework was not established.
Still missing
- A validated gene-specific rule showing that pathogenic CTNNA1 variants are almost exclusively truncating would be needed.
Sources
pvs1_gene_contextPMID:32051609 ↗
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. Details ▾Hide ▴
Evidence considered
- Available records do not provide phase information.
Still missing
- Phase data would be needed.
Sources
BP5 No alternate molecular explanation was identified that would clearly account for the phenotype independently of this variant. Details ▾Hide ▴
Evidence considered
- Available records do not provide sufficient alternate-diagnosis information.
Still missing
- Comprehensive phenotype and alternate-cause data would be needed.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, NM_001903.5:c.1618C>T (p.Arg540Cys), and it does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants, so PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
- Generic PVS1 gene gate is eligible for CTNNA1 loss of function
- but the variant-level scaffold does not place this substitution in a PVS1 bucket.
Sources
PM4 N/APM4 applies to protein length changes such as in-frame insertions/deletions or stop-loss variants, which is not the variant type observed here. Details ▾Hide ▴
Evidence considered
- The variant is a missense substitution.
PM5 N/AA same-residue PM5 comparison was not applied because the available review materials could not safely confirm that classic same-residue PM5 logic should be used for this gene/framework, and no validated comparator variant set was established. Details ▾Hide ▴
Evidence considered
- PM5 candidate review artifact marked classic PM5 semantics as unconfirmed and did not identify validated comparators.
Still missing
- A gene/framework-specific PM5 rule and verified same-residue pathogenic comparators would be needed.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions, which is not the variant type observed here. Details ▾Hide ▴
Evidence considered
- The variant is a missense substitution.
BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splice impact, which is not the variant type observed here. Details ▾Hide ▴
Evidence considered
- The variant is a missense substitution.
Identifiers
- Gene
- CTNNA1
- Transcript
- NM_001903.5
- Coding (HGVS c.)
- NM_001903.5:c.1618C>T
- Protein (HGVS p.)
- NP_001894.2:p.(Arg540Cys)
- GRCh38
- chr5:138924581 C>T
- GRCh37
- chr5:138260270 C>T
- ClinVar
- 661855
- COSMIC
- COSV100242785
Gene diagram
Every interpreted variant in CTNNA1, mapped onto the exon structure of NM_001903.5. Select a row to find it on the plot.
CTNNA1NM_001903.5
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 CTNNA1
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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
11 / 1,613,994 alleles
AF 6.82e-06 · 0 homozygotes · FAF 1.33e-05
gnomAD v2.1
1 / 251,442 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.8e-06 · 11 / 1,613,994 alleles · 0 hom · FAF 1.3e-05
| Admixed American3 / 59,986 | 5e-05 |
| European (non-Finnish)8 / 1,180,052 | 6.8e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,442 alleles · 0 hom
| Admixed American1 / 34,580 | 2.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.305
- BayesDel
- 0.106
How the predictions were used
PP3 Available computational evidence does not provide consistent support for a damaging effect. SpliceAI predicts no meaningful splice impact (max delta score 0.00), REVEL is 0.305, and BayesDel is 0.105968; together these results do not reach a clear PP3 threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL 0.305.
- BayesDel 0.105968.
Still missing
- Additional validated gene-specific computational thresholds could refine this assessment.
Sources
BP4 Available computational evidence does not provide consistent support for a benign effect. SpliceAI is neutral for splicing (max delta score 0.00), but REVEL 0.305 and BayesDel 0.105968 are not sufficiently benign to support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL 0.305.
- BayesDel 0.105968.
Still missing
- Additional validated gene-specific benign computational thresholds could refine this assessment.
Sources
BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splice impact, which is not the variant type observed here. Details ▾Hide ▴
Evidence considered
- The variant is a missense substitution.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.305. BayesDel score = 0.105968.
4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 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.Richards S et al. · 2015No paper-specific finding is recorded.
-
PMID 32051609 ↗Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer.Clark DF et al. · 2020No paper-specific finding is recorded.
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PMID 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.Hampel H et al. · 2015No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,613,994 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
4 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/661855/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-138260270-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-138924581-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-138924581-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001903.5%3Ac.1618…
- OncoKB ↗www.oncokb.org/gene/CTNNA1/R540C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=127066230
- 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= 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.
gnomAD 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).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 661855)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.305. BayesDel score = 0.105968.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100242785, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.