Variant summary: APC c.7619C>A (p.Pro2540Gln) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250632 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7619C>A in individuals affected with Colorectal Cancer Risk and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.7619C>A (p.Pro2540Gln)
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.
(2)
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
2
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.7619C>A (p.Pro2540Gln)
Variation ID: 2691438 Accession: VCV002691438.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112843213 (GRCh38) [ NCBI UCSC ] 5: 112178910 (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 4, 2024 Feb 28, 2024 Dec 28, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.7619C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Pro2540Gln missense NM_001127510.3:c.7619C>A NP_001120982.1:p.Pro2540Gln missense NM_001127511.3:c.7565C>A NP_001120983.2:p.Pro2522Gln missense NM_001354895.2:c.7619C>A NP_001341824.1:p.Pro2540Gln missense NM_001354896.2:c.7673C>A NP_001341825.1:p.Pro2558Gln missense NM_001354897.2:c.7649C>A NP_001341826.1:p.Pro2550Gln missense NM_001354898.2:c.7544C>A NP_001341827.1:p.Pro2515Gln missense NM_001354899.2:c.7535C>A NP_001341828.1:p.Pro2512Gln missense NM_001354900.2:c.7496C>A NP_001341829.1:p.Pro2499Gln missense NM_001354901.2:c.7442C>A NP_001341830.1:p.Pro2481Gln missense NM_001354902.2:c.7346C>A NP_001341831.1:p.Pro2449Gln missense NM_001354903.2:c.7316C>A NP_001341832.1:p.Pro2439Gln missense NM_001354904.2:c.7241C>A NP_001341833.1:p.Pro2414Gln missense NM_001354905.2:c.7139C>A NP_001341834.1:p.Pro2380Gln missense NM_001354906.2:c.6770C>A NP_001341835.1:p.Pro2257Gln missense NM_001407446.1:c.7703C>A NP_001394375.1:p.Pro2568Gln missense NM_001407447.1:c.7673C>A NP_001394376.1:p.Pro2558Gln missense NM_001407448.1:c.7673C>A NP_001394377.1:p.Pro2558Gln missense NM_001407449.1:c.7673C>A NP_001394378.1:p.Pro2558Gln missense NM_001407450.1:c.7619C>A NP_001394379.1:p.Pro2540Gln missense NM_001407451.1:c.7598C>A NP_001394380.1:p.Pro2533Gln missense NM_001407452.1:c.7589C>A NP_001394381.1:p.Pro2530Gln missense NM_001407453.1:c.7442C>A NP_001394382.1:p.Pro2481Gln missense NM_001407454.1:c.7370C>A NP_001394383.1:p.Pro2457Gln missense NM_001407455.1:c.7370C>A NP_001394384.1:p.Pro2457Gln missense NM_001407456.1:c.7370C>A NP_001394385.1:p.Pro2457Gln missense NM_001407457.1:c.7370C>A NP_001394386.1:p.Pro2457Gln missense NM_001407458.1:c.7316C>A NP_001394387.1:p.Pro2439Gln missense NM_001407459.1:c.7316C>A NP_001394388.1:p.Pro2439Gln missense NM_001407460.1:c.7316C>A NP_001394389.1:p.Pro2439Gln missense NM_001407467.1:c.7232C>A NP_001394396.1:p.Pro2411Gln missense NM_001407469.1:c.7232C>A NP_001394398.1:p.Pro2411Gln missense NM_001407470.1:c.6770C>A NP_001394399.1:p.Pro2257Gln missense NM_001407471.1:c.6467C>A NP_001394400.1:p.Pro2156Gln missense NM_001407472.1:c.6467C>A NP_001394401.1:p.Pro2156Gln missense NR_176365.1:n.7454C>A non-coding transcript variant NR_176366.1:n.7873C>A non-coding transcript variant NC_000005.10:g.112843213C>A NC_000005.9:g.112178910C>A NG_008481.4:g.155693C>A LRG_130:g.155693C>A LRG_130t1:c.7619C>A LRG_130p1:p.Pro2540Gln LRG_130t2:c.7619C>A LRG_130p2:p.Pro2540Gln LRG_130t3:c.7619C>A LRG_130p3:p.Pro2540Gln - Protein change
- P2156Q, P2257Q, P2380Q, P2411Q, P2414Q, P2439Q, P2449Q, P2457Q, P2481Q, P2499Q, P2512Q, P2515Q, P2522Q, P2530Q, P2533Q, P2540Q, P2550Q, P2558Q, P2568Q
- Other names
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- Canonical SPDI
- NC_000005.10:112843212:C: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. |
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| APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14965 | 15103 | |
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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Dec 28, 2023 | RCV003489688.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Feb 20, 2023 | RCV003779282.2 |
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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Uncertain significance
(Dec 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241741.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: APC c.7619C>A (p.Pro2540Gln) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded … (more)
Variant summary: APC c.7619C>A (p.Pro2540Gln) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250632 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7619C>A in individuals affected with Colorectal Cancer Risk and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Feb 20, 2023)
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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: SCV004680008.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2540 of the APC protein (p.Pro2540Gln). … (more)
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2540 of the APC protein (p.Pro2540Gln). This variant is present in population databases (rs777667481, gnomAD 0.0009%). 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. 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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Comment:
Comment:
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2540 of the APC protein (p.Pro2540Gln). This variant is present in population databases (rs777667481, gnomAD 0.0009%). 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. 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.
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:
Variant summary: APC c.7619C>A (p.Pro2540Gln) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250632 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7619C>A in individuals affected with Colorectal Cancer Risk and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2540 of the APC protein (p.Pro2540Gln). This variant is present in population databases (rs777667481, gnomAD 0.0009%). 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. 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.
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 Sep 30, 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.