Variant summary: APC c.4831C>T (p.Gln1611X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246062 control chromosomes. c.4831C>T has been reported in the literature in an individual affected with Familial Adenomatous Polyposis (Lagarde 2010). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.4831C>T (p.Gln1611Ter)
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.
(4)
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/Likely pathogenic
4
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.4831C>T (p.Gln1611Ter)
Variation ID: 449336 Accession: VCV000449336.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112840425 (GRCh38) [ NCBI UCSC ] 5: 112176122 (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 Dec 19, 2017 Feb 14, 2024 May 12, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.4831C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Gln1611Ter nonsense NM_001127510.3:c.4831C>T NP_001120982.1:p.Gln1611Ter nonsense NM_001127511.3:c.4777C>T NP_001120983.2:p.Gln1593Ter nonsense NM_001354895.2:c.4831C>T NP_001341824.1:p.Gln1611Ter nonsense NM_001354896.2:c.4885C>T NP_001341825.1:p.Gln1629Ter nonsense NM_001354897.2:c.4861C>T NP_001341826.1:p.Gln1621Ter nonsense NM_001354898.2:c.4756C>T NP_001341827.1:p.Gln1586Ter nonsense NM_001354899.2:c.4747C>T NP_001341828.1:p.Gln1583Ter nonsense NM_001354900.2:c.4708C>T NP_001341829.1:p.Gln1570Ter nonsense NM_001354901.2:c.4654C>T NP_001341830.1:p.Gln1552Ter nonsense NM_001354902.2:c.4558C>T NP_001341831.1:p.Gln1520Ter nonsense NM_001354903.2:c.4528C>T NP_001341832.1:p.Gln1510Ter nonsense NM_001354904.2:c.4453C>T NP_001341833.1:p.Gln1485Ter nonsense NM_001354905.2:c.4351C>T NP_001341834.1:p.Gln1451Ter nonsense NM_001354906.2:c.3982C>T NP_001341835.1:p.Gln1328Ter nonsense NC_000005.10:g.112840425C>T NC_000005.9:g.112176122C>T NG_008481.4:g.152905C>T LRG_130:g.152905C>T - Protein change
- Q1593*, Q1611*, Q1328*, Q1451*, Q1570*, Q1629*, Q1485*, Q1520*, Q1583*, Q1621*, Q1510*, Q1552*, Q1586*
- Other names
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- Canonical SPDI
- NC_000005.10:112840424:C: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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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Aug 12, 2019 | RCV000521142.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Mar 23, 2018 | RCV000780834.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 12, 2023 | RCV004561494.2 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Mar 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918434.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: APC c.4831C>T (p.Gln1611X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: APC c.4831C>T (p.Gln1611X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246062 control chromosomes. c.4831C>T has been reported in the literature in an individual affected with Familial Adenomatous Polyposis (Lagarde 2010). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
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Pathogenic
(Aug 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617343.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population … (more)
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Disrupts a critical functional domain: 20-aa repeat beta-catenin down-regulating domain, SAMP repeats/Axin binding domain, basic domain, EB1 binding domain, and hDLG binding domain (Azzopardi 2008); This variant is associated with the following publications: (PMID: 20685668, 12494469) (less)
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Pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004045620.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
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Pathogenic
(Apr 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001585144.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. 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 has been observed in individual(s) with familial adenomatous polyposis (PMID: 20685668, 14961559). This variant is also known as 3982C>T (Q1328X) in the literature. ClinVar contains an entry for this variant (Variation ID: 449336). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Gln1611*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1233 amino acids of the APC protein. (less)
|
Comment:
Comment:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Disrupts a critical functional domain: 20-aa repeat beta-catenin down-regulating domain, SAMP repeats/Axin binding domain, basic domain, EB1 binding domain, and hDLG binding domain (Azzopardi 2008); This variant is associated with the following publications: (PMID: 20685668, 12494469)
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
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. 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 has been observed in individual(s) with familial adenomatous polyposis (PMID: 20685668, 14961559). This variant is also known as 3982C>T (Q1328X) in the literature. ClinVar contains an entry for this variant (Variation ID: 449336). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Gln1611*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1233 amino acids 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.4831C>T (p.Gln1611X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246062 control chromosomes. c.4831C>T has been reported in the literature in an individual affected with Familial Adenomatous Polyposis (Lagarde 2010). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Disrupts a critical functional domain: 20-aa repeat beta-catenin down-regulating domain, SAMP repeats/Axin binding domain, basic domain, EB1 binding domain, and hDLG binding domain (Azzopardi 2008); This variant is associated with the following publications: (PMID: 20685668, 12494469)
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
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. 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 has been observed in individual(s) with familial adenomatous polyposis (PMID: 20685668, 14961559). This variant is also known as 3982C>T (Q1328X) in the literature. ClinVar contains an entry for this variant (Variation ID: 449336). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Gln1611*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1233 amino acids 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 |
| Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. | Lagarde A | Journal of medical genetics | 2010 | PMID: 20685668 |
| 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 |
| The mutation spectrum of the APC gene in FAP patients from southern Italy: detection of known and four novel mutations. | De Rosa M | Human mutation | 2003 | PMID: 14961559 |
| Analysis of the human APC mutation spectrum in a saccharomyces cerevisiae strain with a mismatch repair defect. | Otsuka K | International journal of cancer | 2003 | PMID: 12494469 |
| 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 rs774847203 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.