ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.4612_4613del (p.Glu1538fs)
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.4612_4613del (p.Glu1538fs)
Variation ID: 823 Accession: VCV000000823.21
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 5q22.2 5: 112840205-112840206 (GRCh38) [ NCBI UCSC ] 5: 112175902-112175903 (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 Sep 14, 2013 Jun 17, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.4612_4613del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Glu1538fs frameshift NM_000038.5:c.4612_4613delGA NM_001127510.3:c.4612_4613del NP_001120982.1:p.Glu1538fs frameshift NM_001127511.3:c.4558_4559del NP_001120983.2:p.Glu1520fs frameshift NM_001354895.2:c.4612_4613del NP_001341824.1:p.Glu1538fs frameshift NM_001354896.2:c.4666_4667del NP_001341825.1:p.Glu1556fs frameshift NM_001354897.2:c.4642_4643del NP_001341826.1:p.Glu1548fs frameshift NM_001354898.2:c.4537_4538del NP_001341827.1:p.Glu1513fs frameshift NM_001354899.2:c.4528_4529del NP_001341828.1:p.Glu1510fs frameshift NM_001354900.2:c.4489_4490del NP_001341829.1:p.Glu1497fs frameshift NM_001354901.2:c.4435_4436del NP_001341830.1:p.Glu1479fs frameshift NM_001354902.2:c.4339_4340del NP_001341831.1:p.Glu1447fs frameshift NM_001354903.2:c.4309_4310del NP_001341832.1:p.Glu1437fs frameshift NM_001354904.2:c.4234_4235del NP_001341833.1:p.Glu1412fs frameshift NM_001354905.2:c.4132_4133del NP_001341834.1:p.Glu1378fs frameshift NM_001354906.2:c.3763_3764del NP_001341835.1:p.Glu1255fs frameshift NC_000005.10:g.112840206_112840207del NC_000005.9:g.112175903_112175904del NG_008481.4:g.152685_152686del NG_008481.4:g.152686_152687del LRG_130:g.152686_152687del - Protein change
- E1255fs, E1378fs, E1412fs, E1447fs, E1479fs, E1497fs, E1510fs, E1520fs, E1538fs, E1437fs, E1513fs, E1548fs, E1556fs
- Other names
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- Canonical SPDI
- NC_000005.10:112840204:AGA: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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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 | ||
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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
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 |
14931 | 15069 |
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
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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) |
no assertion criteria provided
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Jan 1, 1997 | RCV000000866.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 20, 2020 | RCV001781152.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2015 | RCV002336071.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2023 | RCV002512626.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2021 | RCV003227591.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2020 | RCV004017217.2 |
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 20, 2020)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002067521.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Pathogenic
(Dec 13, 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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Invitae
Accession: SCV000768087.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu1538Ilefs*5) 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.Glu1538Ilefs*5) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1306 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: 8162051, 8594558, 20223039, 20513532, 20685668, 21643010, 21779980, 22987206). ClinVar contains an entry for this variant (Variation ID: 823). 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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Pathogenic
(Jul 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial multiple polyposis syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848434.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Glu1538IlefsX5 variant in APC has been previously reported in at least 6 individuals with APC-associated polyposis conditions: 3 with familial adenomatous polyposis (FAP), 3 … (more)
The p.Glu1538IlefsX5 variant in APC has been previously reported in at least 6 individuals with APC-associated polyposis conditions: 3 with familial adenomatous polyposis (FAP), 3 individuals with Gardner syndrome, and 4 individuals with suspected FAP (Gayther 1994 PMID: 8162051, Armstrong 1997 PMID: 9375853, Friedl 2005 PMID: 20223039, Jang 2010 PMID: 20513532, Lagarde 2010 PMID: 20685668, Jarry 2011 PMID: 21779980, Rohlin 2011 PMID: 21643010, Schwarzová 2013 PMID: 22987206). This variant was also reported by other clinical laboratories in ClinVar (Variation ID: 823) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1538 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~46% of the coding region, with 1302 amino acids removed. Truncating variants in the last exon of APC, including multiple variants downstream of this variant, have been reported in individuals with FAP. Furthermore, this truncation is predicted to remove the EB1 and APC-basic domains of the APC protein, and in vitro studies have shown that these domains are important regions for APC-mediated microtubule stability and F-actin interactions (Moseley 2007 PMID 17293347, Wen 2004 PMID 15311282). In summary, this variant meets criteria to be classified as pathogenic for APC-associated polyposis conditions, including autosomal dominant FAP and Gardner syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Strong. (less)
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Pathogenic
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer
Familial adenomatous polyposis 1 Desmoid disease, hereditary Familial adenomatous polyposis 1 Hepatocellular carcinoma Gastric cancer Gastric adenocarcinoma and proximal polyposis of the stomach Familial adenomatous polyposis 1 Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003924235.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
APC NM_000038.5 exon 15 p.Glu1538Ilefsx5 (c.4612_4613del): This variant has been reported in the literature in at least 8 individuals with Familial Adenomatous Polyposis (FAP) (Gayther … (more)
APC NM_000038.5 exon 15 p.Glu1538Ilefsx5 (c.4612_4613del): This variant has been reported in the literature in at least 8 individuals with Familial Adenomatous Polyposis (FAP) (Gayther 1994 PMID:8162051, Friedl 2005 PMID:20223039, Jang 2010 PMID:20513532, Lagarde 2010 PMID:20685668, Jarry 2011 PMID:21779980, Rohlin 2011 PMID:21643010, Schwarzova 2013 PMID:22987206). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:823). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of two nucleotides and creates a premature stop codon 5 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Zhang 2017 PMID:28423402). Of note, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. However this variant is predicted to affect approximately 45% of the protein and other variants downstream have been reported as Pathogenic. Furthermore, evidence in the literature suggests that variants cluster in this region (Gayther 1994 PMID:8162051). In summary, this variant is classified as pathogenic based on the data above. (less)
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Pathogenic
(May 11, 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: SCV004044003.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Jul 28, 2015)
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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: SCV002639069.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.4612_4613delGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 4612 and … (more)
The c.4612_4613delGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 4612 and 4613, causing a translational frameshift with a predicted alternate stop codon. This mutation has been detected in multiple individuals with clinical diagnoses of AFAP or FAP (Friedl W, et al. Hered Cancer Clin Pract 2005;3(3):95-114, Vandrovcová J, et a. Hum. Mutat. 2004;23(4):397, Jang YH, et al. Cancer Genet. Cytogenet. 2010;200(1):34-9, Gayther SA, et al. Hum. Mol. Genet. 1994;3(1):53-6, Armstrong JG, et al. Hum. Mutat. 1997;10(5):376-80). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
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Pathogenic
(Nov 28, 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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Baylor Genetics
Accession: SCV004200474.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 01, 1997)
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no assertion criteria provided
Method: literature only
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GARDNER SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021016.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2013 |
Comment on evidence:
In 2 previously reported patients with severe Gardner phenotype (see 175100) (Davies et al., 1995), Armstrong et al. (1997) identified a 2-bp deletion (1538delAG) in … (more)
In 2 previously reported patients with severe Gardner phenotype (see 175100) (Davies et al., 1995), Armstrong et al. (1997) identified a 2-bp deletion (1538delAG) in the APC gene, resulting in a frameshift and premature termination. The patients were of different ethnic backgrounds and had different haplotypes, suggesting that the same mutation had arisen in 2 separate populations. (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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Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation. | Ikenoue T | Human genome variation | 2015 | PMID: 27081525 |
Novel mutations of the APC gene and genetic consequences of splicing mutations in the Czech FAP families. | Schwarzová L | Familial cancer | 2013 | PMID: 22987206 |
Prevalence of skin lesions in familial adenomatous polyposis: a marker for presymptomatic diagnosis? | Burger B | The oncologist | 2011 | PMID: 22135120 |
A survey of APC mutations in Quebec. | Jarry J | Familial cancer | 2011 | PMID: 21779980 |
Inactivation of promoter 1B of APC causes partial gene silencing: evidence for a significant role of the promoter in regulation and causative of familial adenomatous polyposis. | Rohlin A | Oncogene | 2011 | PMID: 21643010 |
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 |
Three novel mutations of the APC gene in Korean patients with familial adenomatous polyposis. | Jang YH | Cancer genetics and cytogenetics | 2010 | PMID: 20513532 |
Regulated binding of adenomatous polyposis coli protein to actin. | Moseley JB | The Journal of biological chemistry | 2007 | PMID: 17293347 |
Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. | Friedl W | Hereditary cancer in clinical practice | 2005 | PMID: 20223039 |
EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. | Wen Y | Nature cell biology | 2004 | PMID: 15311282 |
Molecular analysis of the APC and MYH genes in Czech families affected by FAP or multiple adenomas: 13 novel mutations. | Vandrovcová J | Human mutation | 2004 | PMID: 15024739 |
Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. | Brensinger JD | Gut | 1998 | PMID: 9824584 |
APC mutations in familial adenomatous polyposis families in the Northwest of England. | Armstrong JG | Human mutation | 1997 | PMID: 9375853 |
APC gene: database of germline and somatic mutations in human tumors and cell lines. | Béroud C | Nucleic acids research | 1996 | PMID: 8594558 |
Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. | Davies DR | American journal of human genetics | 1995 | PMID: 7485167 |
Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli. | Gayther SA | Human molecular genetics | 1994 | PMID: 8162051 |
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 |
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Text-mined citations for rs387906236 ...
HelpRecord last updated Aug 18, 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.