This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2469 of the APC protein (p.Ser2469Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.7405T>A (p.Ser2469Thr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(3)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.7405T>A (p.Ser2469Thr)
Variation ID: 2889310 Accession: VCV002889310.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112842999 (GRCh38) [ NCBI UCSC ] 5: 112178696 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2024 Aug 11, 2024 Mar 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.7405T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Ser2469Thr missense NM_000038.5:c.7405T>A NM_001127510.3:c.7405T>A NP_001120982.1:p.Ser2469Thr missense NM_001127511.3:c.7351T>A NP_001120983.2:p.Ser2451Thr missense NM_001354895.2:c.7405T>A NP_001341824.1:p.Ser2469Thr missense NM_001354896.2:c.7459T>A NP_001341825.1:p.Ser2487Thr missense NM_001354897.2:c.7435T>A NP_001341826.1:p.Ser2479Thr missense NM_001354898.2:c.7330T>A NP_001341827.1:p.Ser2444Thr missense NM_001354899.2:c.7321T>A NP_001341828.1:p.Ser2441Thr missense NM_001354900.2:c.7282T>A NP_001341829.1:p.Ser2428Thr missense NM_001354901.2:c.7228T>A NP_001341830.1:p.Ser2410Thr missense NM_001354902.2:c.7132T>A NP_001341831.1:p.Ser2378Thr missense NM_001354903.2:c.7102T>A NP_001341832.1:p.Ser2368Thr missense NM_001354904.2:c.7027T>A NP_001341833.1:p.Ser2343Thr missense NM_001354905.2:c.6925T>A NP_001341834.1:p.Ser2309Thr missense NM_001354906.2:c.6556T>A NP_001341835.1:p.Ser2186Thr missense NM_001407446.1:c.7489T>A NP_001394375.1:p.Ser2497Thr missense NM_001407447.1:c.7459T>A NP_001394376.1:p.Ser2487Thr missense NM_001407448.1:c.7459T>A NP_001394377.1:p.Ser2487Thr missense NM_001407449.1:c.7459T>A NP_001394378.1:p.Ser2487Thr missense NM_001407450.1:c.7405T>A NP_001394379.1:p.Ser2469Thr missense NM_001407451.1:c.7384T>A NP_001394380.1:p.Ser2462Thr missense NM_001407452.1:c.7375T>A NP_001394381.1:p.Ser2459Thr missense NM_001407453.1:c.7228T>A NP_001394382.1:p.Ser2410Thr missense NM_001407454.1:c.7156T>A NP_001394383.1:p.Ser2386Thr missense NM_001407455.1:c.7156T>A NP_001394384.1:p.Ser2386Thr missense NM_001407456.1:c.7156T>A NP_001394385.1:p.Ser2386Thr missense NM_001407457.1:c.7156T>A NP_001394386.1:p.Ser2386Thr missense NM_001407458.1:c.7102T>A NP_001394387.1:p.Ser2368Thr missense NM_001407459.1:c.7102T>A NP_001394388.1:p.Ser2368Thr missense NM_001407460.1:c.7102T>A NP_001394389.1:p.Ser2368Thr missense NM_001407467.1:c.7018T>A NP_001394396.1:p.Ser2340Thr missense NM_001407469.1:c.7018T>A NP_001394398.1:p.Ser2340Thr missense NM_001407470.1:c.6556T>A NP_001394399.1:p.Ser2186Thr missense NM_001407471.1:c.6253T>A NP_001394400.1:p.Ser2085Thr missense NM_001407472.1:c.6253T>A NP_001394401.1:p.Ser2085Thr missense NR_176365.1:n.7240T>A non-coding transcript variant NR_176366.1:n.7659T>A non-coding transcript variant NC_000005.10:g.112842999T>A NC_000005.9:g.112178696T>A NG_008481.4:g.155479T>A LRG_130:g.155479T>A LRG_130t1:c.7405T>A LRG_130p1:p.Ser2469Thr LRG_130t2:c.7405T>A LRG_130p2:p.Ser2469Thr LRG_130t3:c.7405T>A LRG_130p3:p.Ser2469Thr - Protein change
- S2368T, S2469T, S2309T, S2343T, S2378T, S2428T, S2441T, S2386T, S2444T, S2451T, S2459T, S2462T, S2085T, S2186T, S2340T, S2410T, S2479T, S2487T, S2497T
- Other names
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- Canonical SPDI
- NC_000005.10:112842998:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14969 | 15107 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
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Oct 6, 2023 | RCV004005815.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 13, 2024 | RCV004565921.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 19, 2024 | RCV004654314.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Uncertain significance
(Jan 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004515341.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2469 of the APC protein (p.Ser2469Thr). … (more)
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2469 of the APC protein (p.Ser2469Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
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Uncertain Significance
(Oct 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Classic or attenuated familial adenomatous polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004834875.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces serine with threonine at codon 2469 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with threonine at codon 2469 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV005149281.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The p.S2469T variant (also known as c.7405T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide … (more)
The p.S2469T variant (also known as c.7405T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 7405. The serine at codon 2469 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
|
Comment:
Comment:
This missense variant replaces serine with threonine at codon 2469 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.S2469T variant (also known as c.7405T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 7405. The serine at codon 2469 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this alteration remains unclear.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2469 of the APC protein (p.Ser2469Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces serine with threonine at codon 2469 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.S2469T variant (also known as c.7405T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 7405. The serine at codon 2469 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for this variant ...
HelpRecord last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.