This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.4666del (p.Thr1556fs)
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.
(3)
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
3
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.4666del (p.Thr1556fs)
Variation ID: 156477 Accession: VCV000156477.5
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112840255 (GRCh38) [ NCBI UCSC ] 5: 112175952 (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 Oct 20, 2014 Feb 14, 2024 May 11, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.4666del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Thr1556fs frameshift NM_001127510.3:c.4666del NP_001120982.1:p.Thr1556fs frameshift NM_001127511.3:c.4612del NP_001120983.2:p.Thr1538fs frameshift NM_001354895.2:c.4666del NP_001341824.1:p.Thr1556fs frameshift NM_001354896.2:c.4720del NP_001341825.1:p.Thr1574fs frameshift NM_001354897.2:c.4696del NP_001341826.1:p.Thr1566fs frameshift NM_001354898.2:c.4591del NP_001341827.1:p.Thr1531fs frameshift NM_001354899.2:c.4582del NP_001341828.1:p.Thr1528fs frameshift NM_001354900.2:c.4543del NP_001341829.1:p.Thr1515fs frameshift NM_001354901.2:c.4489del NP_001341830.1:p.Thr1497fs frameshift NM_001354902.2:c.4393del NP_001341831.1:p.Thr1465fs frameshift NM_001354903.2:c.4363del NP_001341832.1:p.Thr1455fs frameshift NM_001354904.2:c.4288del NP_001341833.1:p.Thr1430fs frameshift NM_001354905.2:c.4186del NP_001341834.1:p.Thr1396fs frameshift NM_001354906.2:c.3817del NP_001341835.1:p.Thr1273fs frameshift NC_000005.10:g.112840260del NC_000005.9:g.112175957del NG_008481.4:g.152740del LRG_130:g.152740del - Protein change
- T1497fs, T1515fs, T1566fs, T1273fs, T1396fs, T1531fs, T1538fs, T1430fs, T1455fs, T1528fs, T1556fs, T1574fs, T1465fs
- Other names
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- Canonical SPDI
- NC_000005.10:112840254:AAAAAA:AAAAA
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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 |
15241 | 15379 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV000144566.5 |
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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Pathogenic
(May 11, 2023)
|
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: SCV004043963.2
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
(Jun 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: SCV003439249.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 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. ClinVar contains an entry for this variant (Variation ID: 156477). This premature translational stop signal has been observed in individual(s) with clinical features of APC-related conditions (PMID: 15095859). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1556Leufs*9) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1288 amino acid(s) of the APC protein. (less)
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Pathogenic
(Jul 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Adenomatous polyposis coli
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000189859.1
First in ClinVar: Oct 20, 2014 Last updated: Oct 20, 2014 |
|
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. ClinVar contains an entry for this variant (Variation ID: 156477). This premature translational stop signal has been observed in individual(s) with clinical features of APC-related conditions (PMID: 15095859). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1556Leufs*9) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1288 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:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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. ClinVar contains an entry for this variant (Variation ID: 156477). This premature translational stop signal has been observed in individual(s) with clinical features of APC-related conditions (PMID: 15095859). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1556Leufs*9) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1288 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 |
| Unexplained polyposis: a challenge for geneticists, pathologists and gastroenterologists. | Mongin C | Clinical genetics | 2012 | PMID: 21476993 |
| 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 |
| 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 |
| A case of Gardner syndrome with a mutation at codon 1556 of APC: a suggested case of genotype-phenotype correlation in dental abnormality. | Oku T | European journal of gastroenterology & hepatology | 2004 | PMID: 15095859 |
| 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 |
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Text-mined citations for rs587783031 ...
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 25, 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.