ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.3867T>A (p.Cys1289Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.3867T>A (p.Cys1289Ter)
Variation ID: 545962 Accession: VCV000545962.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112839461 (GRCh38) [ NCBI UCSC ] 5: 112175158 (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 Jul 9, 2018 Feb 14, 2024 May 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.3867T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Cys1289Ter nonsense NM_001127510.3:c.3867T>A NP_001120982.1:p.Cys1289Ter nonsense NM_001127511.3:c.3813T>A NP_001120983.2:p.Cys1271Ter nonsense NM_001354895.2:c.3867T>A NP_001341824.1:p.Cys1289Ter nonsense NM_001354896.2:c.3921T>A NP_001341825.1:p.Cys1307Ter nonsense NM_001354897.2:c.3897T>A NP_001341826.1:p.Cys1299Ter nonsense NM_001354898.2:c.3792T>A NP_001341827.1:p.Cys1264Ter nonsense NM_001354899.2:c.3783T>A NP_001341828.1:p.Cys1261Ter nonsense NM_001354900.2:c.3744T>A NP_001341829.1:p.Cys1248Ter nonsense NM_001354901.2:c.3690T>A NP_001341830.1:p.Cys1230Ter nonsense NM_001354902.2:c.3594T>A NP_001341831.1:p.Cys1198Ter nonsense NM_001354903.2:c.3564T>A NP_001341832.1:p.Cys1188Ter nonsense NM_001354904.2:c.3489T>A NP_001341833.1:p.Cys1163Ter nonsense NM_001354905.2:c.3387T>A NP_001341834.1:p.Cys1129Ter nonsense NM_001354906.2:c.3018T>A NP_001341835.1:p.Cys1006Ter nonsense NC_000005.10:g.112839461T>A NC_000005.9:g.112175158T>A NG_008481.4:g.151941T>A LRG_130:g.151941T>A - Protein change
- C1271*, C1289*, C1006*, C1129*, C1230*, C1248*, C1307*, C1163*, C1198*, C1264*, C1188*, C1261*, C1299*
- Other names
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- Canonical SPDI
- NC_000005.10:112839460: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
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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
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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 |
14091 | 14225 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 14, 2016 | RCV000657604.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763543.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV002360677.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 9, 2023 | RCV003337333.2 |
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
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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
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer
Hepatocellular carcinoma Desmoid disease, hereditary Familial adenomatous polyposis 1 Familial adenomatous polyposis 1 Gastric cancer
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894356.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jul 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000779346.2
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
Comment:
This variant is denoted APC c.3867T>A at the cDNA level and p.Cys1289Ter (C1289X) at the protein level. The substitution creates a nonsense variant, which changes … (more)
This variant is denoted APC c.3867T>A at the cDNA level and p.Cys1289Ter (C1289X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TGA), and is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in individuals with a clinical diagnosis of Familial Adenomatous Polyposis (FAP) and is considered pathogenic (Won 1999, Kerr 2013). (less)
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Pathogenic
(Feb 01, 2019)
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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: SCV002624788.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.C1289* pathogenic mutation (also known as c.3867T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at … (more)
The p.C1289* pathogenic mutation (also known as c.3867T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 3867. This changes the amino acid from a cysteine to a stop codon within coding exon 15. This alteration was identified in a Korean patient with polyposis and colorectal cancer but who did not manifest extracolonic features associated with FAP (Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Won YJ et al. J. Hum. Genet. 1999;44:103-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 09, 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:
unknown
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Myriad Genetics, Inc.
Accession: SCV004043227.2
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 13, 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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Invitae
Accession: SCV002229736.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys1289*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Cys1289*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1555 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 10083733). ClinVar contains an entry for this variant (Variation ID: 545962). 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. 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. For these reasons, this variant has been classified as Pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. | Schell MJ | Nature communications | 2016 | PMID: 27302369 |
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 |
Mutation spectrum of the APC gene in 83 Korean FAP families. | Kim DW | Human mutation | 2005 | PMID: 16088911 |
EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. | Wen Y | Nature cell biology | 2004 | PMID: 15311282 |
Germline mutations of the APC gene in Korean familial adenomatous polyposis patients. | Won YJ | Journal of human genetics | 1999 | PMID: 10083733 |
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 rs1554085355 ...
HelpRecord last updated Apr 20, 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.