This deletion of four nucleotides in APC is denoted c.3366_3369delTCAA at the cDNA level and p.Asn1122LysfsX3 (N1122KfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTAA[delTCAA]AATG. The deletion causes a frameshift which changes an Asparagine to a Lysine at codon 1122, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. APC c.3366_3369delTCAA has been observed in at least two individuals with familial adenomatous polyposis (Nagase 1992, Andresen 2009). We consider this variant to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.3366_3369del (p.Asn1122fs)
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
-
NM_000038.6(APC):c.3366_3369del (p.Asn1122fs)
Variation ID: 817033 Accession: VCV000817033.10
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 5q22.2 5: 112838958-112838961 (GRCh38) [ NCBI UCSC ] 5: 112174655-112174658 (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 Mar 16, 2020 Feb 14, 2024 Feb 21, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.3366_3369del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Asn1122fs frameshift NM_001127510.3:c.3366_3369del NP_001120982.1:p.Asn1122fs frameshift NM_001127511.3:c.3312_3315del NP_001120983.2:p.Asn1104fs frameshift NM_001354895.2:c.3366_3369del NP_001341824.1:p.Asn1122fs frameshift NM_001354896.2:c.3420_3423del NP_001341825.1:p.Asn1140fs frameshift NM_001354897.2:c.3396_3399del NP_001341826.1:p.Asn1132fs frameshift NM_001354898.2:c.3291_3294del NP_001341827.1:p.Asn1097fs frameshift NM_001354899.2:c.3282_3285del NP_001341828.1:p.Asn1094fs frameshift NM_001354900.2:c.3243_3246del NP_001341829.1:p.Asn1081fs frameshift NM_001354901.2:c.3189_3192del NP_001341830.1:p.Asn1063fs frameshift NM_001354902.2:c.3093_3096del NP_001341831.1:p.Asn1031fs frameshift NM_001354903.2:c.3063_3066del NP_001341832.1:p.Asn1021fs frameshift NM_001354904.2:c.2988_2991del NP_001341833.1:p.Asn996fs frameshift NM_001354905.2:c.2886_2889del NP_001341834.1:p.Asn962fs frameshift NM_001354906.2:c.2517_2520del NP_001341835.1:p.Asn839fs frameshift NC_000005.10:g.112838960_112838963del NC_000005.9:g.112174657_112174660del NG_008481.4:g.151440_151443del LRG_130:g.151440_151443del - Protein change
- N1031fs, N839fs, N1122fs, N1132fs, N1021fs, N1063fs, N1081fs, N1097fs, N1140fs, N962fs, N1094fs, N1104fs, N996fs
- Other names
- -
- Canonical SPDI
- NC_000005.10:112838957:AATCAA:AA
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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.
- -
- 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. |
|||
| 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
|
May 31, 2018 | RCV001008089.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 21, 2022 | RCV001844255.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 10, 2020 | RCV004563620.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001167834.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
This deletion of four nucleotides in APC is denoted c.3366_3369delTCAA at the cDNA level and p.Asn1122LysfsX3 (N1122KfsX3) at the protein level. The normal sequence, with … (more)
This deletion of four nucleotides in APC is denoted c.3366_3369delTCAA at the cDNA level and p.Asn1122LysfsX3 (N1122KfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTAA[delTCAA]AATG. The deletion causes a frameshift which changes an Asparagine to a Lysine at codon 1122, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. APC c.3366_3369delTCAA has been observed in at least two individuals with familial adenomatous polyposis (Nagase 1992, Andresen 2009). We consider this variant to be pathogenic. (less)
|
|
|
Pathogenic
(Feb 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial multiple polyposis syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103447.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: APC c.3366_3369delTCAA (p.Asn1122LysfsX3) 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.3366_3369delTCAA (p.Asn1122LysfsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250582 control chromosomes. c.3366_3369delTCAA has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Nagase_1992, Wallis_1999, Andresen_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001587936.4
First in ClinVar: May 10, 2021 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. This variant has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 1338764, 19444466, 9950360). 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.Asn1122Lysfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1722 amino acids of the APC protein. (less)
|
Comment:
Comment:
Variant summary: APC c.3366_3369delTCAA (p.Asn1122LysfsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250582 control chromosomes. c.3366_3369delTCAA has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Nagase_1992, Wallis_1999, Andresen_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite 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 been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 1338764, 19444466, 9950360). 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.Asn1122Lysfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1722 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:
This deletion of four nucleotides in APC is denoted c.3366_3369delTCAA at the cDNA level and p.Asn1122LysfsX3 (N1122KfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTAA[delTCAA]AATG. The deletion causes a frameshift which changes an Asparagine to a Lysine at codon 1122, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. APC c.3366_3369delTCAA has been observed in at least two individuals with familial adenomatous polyposis (Nagase 1992, Andresen 2009). We consider this variant to be pathogenic.
Comment:
Variant summary: APC c.3366_3369delTCAA (p.Asn1122LysfsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250582 control chromosomes. c.3366_3369delTCAA has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Nagase_1992, Wallis_1999, Andresen_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite 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 been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 1338764, 19444466, 9950360). 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.Asn1122Lysfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1722 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 |
| APC mutation spectrum of Norwegian familial adenomatous polyposis families: high ratio of novel mutations. | Andresen PA | Journal of cancer research and clinical oncology | 2009 | PMID: 19444466 |
| 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 |
| Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study. | Groves CJ | Gut | 2002 | PMID: 11950808 |
| Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition. | Wallis YL | Journal of medical genetics | 1999 | PMID: 9950360 |
| 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 |
| Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients. | Nagase H | Human mutation | 1992 | PMID: 1338764 |
| 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 rs1580634573 ...
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.