Variant summary: APC c.5133delT (p.Glu1712AsnfsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. While this variant is not expected to result in nonsense-mediated decay, it is expected to disrupt the last 1132 amino acids of the protein, which encode the basic domain (IPR009234) and EB-1 binding domain (IPR009232). At least one variant downstream of this position, namely c.5582_5585delCTTT (p.Ser1861X), has been reported as pathogenic by our laboratory. The variant was absent in 250026 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5133delT in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.5133del (p.Glu1712fs)
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.
Pathogenic
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.5133del (p.Glu1712fs)
Variation ID: 2027006 Accession: VCV002027006.3
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112840727 (GRCh38) [ NCBI UCSC ] 5: 112176424 (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 8, 2023 Feb 20, 2024 Jul 6, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.5133del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Glu1712fs frameshift NM_000038.5:c.5133delT NM_001127510.3:c.5133del NP_001120982.1:p.Glu1712fs frameshift NM_001127511.3:c.5079del NP_001120983.2:p.Glu1694fs frameshift NM_001354895.2:c.5133del NP_001341824.1:p.Glu1712fs frameshift NM_001354896.2:c.5187del NP_001341825.1:p.Glu1730fs frameshift NM_001354897.2:c.5163del NP_001341826.1:p.Glu1722fs frameshift NM_001354898.2:c.5058del NP_001341827.1:p.Glu1687fs frameshift NM_001354899.2:c.5049del NP_001341828.1:p.Glu1684fs frameshift NM_001354900.2:c.5010del NP_001341829.1:p.Glu1671fs frameshift NM_001354901.2:c.4956del NP_001341830.1:p.Glu1653fs frameshift NM_001354902.2:c.4860del NP_001341831.1:p.Glu1621fs frameshift NM_001354903.2:c.4830del NP_001341832.1:p.Glu1611fs frameshift NM_001354904.2:c.4755del NP_001341833.1:p.Glu1586fs frameshift NM_001354905.2:c.4653del NP_001341834.1:p.Glu1552fs frameshift NM_001354906.2:c.4284del NP_001341835.1:p.Glu1429fs frameshift NM_001407446.1:c.5217delT NP_001394375.1:p.Glu1740Asnfs frameshift NM_001407447.1:c.5187delT NP_001394376.1:p.Glu1730Asnfs frameshift NM_001407448.1:c.5187delT NP_001394377.1:p.Glu1730Asnfs frameshift NM_001407449.1:c.5187delT NP_001394378.1:p.Glu1730Asnfs frameshift NM_001407450.1:c.5133delT NP_001394379.1:p.Glu1712Asnfs frameshift NM_001407451.1:c.5112delT NP_001394380.1:p.Glu1705Asnfs frameshift NM_001407452.1:c.5103delT NP_001394381.1:p.Glu1702Asnfs frameshift NM_001407453.1:c.4956delT NP_001394382.1:p.Glu1653Asnfs frameshift NM_001407454.1:c.4884delT NP_001394383.1:p.Glu1629Asnfs frameshift NM_001407455.1:c.4884delT NP_001394384.1:p.Glu1629Asnfs frameshift NM_001407456.1:c.4884delT NP_001394385.1:p.Glu1629Asnfs frameshift NM_001407457.1:c.4884delT NP_001394386.1:p.Glu1629Asnfs frameshift NM_001407458.1:c.4830delT NP_001394387.1:p.Glu1611Asnfs frameshift NM_001407459.1:c.4830delT NP_001394388.1:p.Glu1611Asnfs frameshift NM_001407460.1:c.4830delT NP_001394389.1:p.Glu1611Asnfs frameshift NM_001407467.1:c.4746delT NP_001394396.1:p.Glu1583Asnfs frameshift NM_001407469.1:c.4746delT NP_001394398.1:p.Glu1583Asnfs frameshift NM_001407470.1:c.4284delT NP_001394399.1:p.Glu1429Asnfs frameshift NM_001407471.1:c.3981delT NP_001394400.1:p.Glu1328Asnfs frameshift NM_001407472.1:c.3981delT NP_001394401.1:p.Glu1328Asnfs frameshift NR_176365.1:n.4968delT NR_176366.1:n.5387delT NC_000005.10:g.112840727del NC_000005.9:g.112176424del NG_008481.4:g.153207del LRG_130:g.153207del LRG_130t1:c.5133del LRG_130p1:p.Glu1712Asnfs LRG_130t2:c.5133del LRG_130p2:p.Glu1712Asnfs LRG_130t3:c.5133del LRG_130p3:p.Glu1712Asnfs - Protein change
- E1429fs, E1586fs, E1621fs, E1671fs, E1684fs, E1730fs, E1653fs, E1694fs, E1722fs, E1552fs, E1611fs, E1687fs, E1712fs
- Other names
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- Canonical SPDI
- NC_000005.10:112840726:T:
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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. |
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| Pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2023 | RCV003324050.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2022 | RCV004571388.2 |
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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Pathogenic
(Jul 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial multiple polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004029713.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: APC c.5133delT (p.Glu1712AsnfsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known … (more)
Variant summary: APC c.5133delT (p.Glu1712AsnfsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. While this variant is not expected to result in nonsense-mediated decay, it is expected to disrupt the last 1132 amino acids of the protein, which encode the basic domain (IPR009234) and EB-1 binding domain (IPR009232). At least one variant downstream of this position, namely c.5582_5585delCTTT (p.Ser1861X), has been reported as pathogenic by our laboratory. The variant was absent in 250026 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5133delT in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 26, 2022)
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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: SCV003233064.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be … (more)
For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1712Asnfs*32) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1132 amino acid(s) of the APC protein. (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1712Asnfs*32) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1132 amino acid(s) of the APC protein.
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.5133delT (p.Glu1712AsnfsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. While this variant is not expected to result in nonsense-mediated decay, it is expected to disrupt the last 1132 amino acids of the protein, which encode the basic domain (IPR009234) and EB-1 binding domain (IPR009232). At least one variant downstream of this position, namely c.5582_5585delCTTT (p.Ser1861X), has been reported as pathogenic by our laboratory. The variant was absent in 250026 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5133delT in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1712Asnfs*32) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1132 amino acid(s) of the APC protein.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation. | Ikenoue T | Human genome variation | 2015 | PMID: 27081525 |
| Prevalence of skin lesions in familial adenomatous polyposis: a marker for presymptomatic diagnosis? | Burger B | The oncologist | 2011 | PMID: 22135120 |
| Regulated binding of adenomatous polyposis coli protein to actin. | Moseley JB | The Journal of biological chemistry | 2007 | PMID: 17293347 |
| EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. | Wen Y | Nature cell biology | 2004 | PMID: 15311282 |
| Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. | Brensinger JD | Gut | 1998 | PMID: 9824584 |
| Mutational analysis of patients with adenomatous polyposis: identical inactivating mutations in unrelated individuals. | Groden J | American journal of human genetics | 1993 | PMID: 8381579 |
| Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. | Miyoshi Y | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1316610 |
Text-mined citations for this variant ...
HelpRecord last updated Nov 03, 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.