Frameshift 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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Dobbie 1996, De Rosa 2003, Kanter-Smoler 2008); This variant is associated with the following publications: (PMID: 31269945, 8730280, 18433509, 20685668, 20223039, 14961559, 23159591, 9067764, 7746201)
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.3577_3578del (p.Gln1193fs)
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.
(5)
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
5
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.3577_3578del (p.Gln1193fs)
Variation ID: 411475 Accession: VCV000411475.18
- Type and length
-
Deletion, 2 bp
- Location
-
Cytogenetic: 5q22.2 5: 112839170-112839171 (GRCh38) [ NCBI UCSC ] 5: 112174867-112174868 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 10, 2018 Oct 8, 2024 Oct 17, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.3577_3578del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Gln1193fs frameshift NM_000038.5:c.3577_3578del NM_001127510.3:c.3577_3578del NP_001120982.1:p.Gln1193fs frameshift NM_001127511.3:c.3523_3524del NP_001120983.2:p.Gln1175fs frameshift NM_001354895.2:c.3577_3578del NP_001341824.1:p.Gln1193fs frameshift NM_001354896.2:c.3631_3632del NP_001341825.1:p.Gln1211fs frameshift NM_001354897.2:c.3607_3608del NP_001341826.1:p.Gln1203fs frameshift NM_001354898.2:c.3502_3503del NP_001341827.1:p.Gln1168fs frameshift NM_001354899.2:c.3493_3494del NP_001341828.1:p.Gln1165fs frameshift NM_001354900.2:c.3454_3455del NP_001341829.1:p.Gln1152fs frameshift NM_001354901.2:c.3400_3401del NP_001341830.1:p.Gln1134fs frameshift NM_001354902.2:c.3304_3305del NP_001341831.1:p.Gln1102fs frameshift NM_001354903.2:c.3274_3275del NP_001341832.1:p.Gln1092fs frameshift NM_001354904.2:c.3199_3200del NP_001341833.1:p.Gln1067fs frameshift NM_001354905.2:c.3097_3098del NP_001341834.1:p.Gln1033fs frameshift NM_001354906.2:c.2728_2729del NP_001341835.1:p.Gln910fs frameshift NC_000005.10:g.112839171_112839172del NC_000005.9:g.112174868_112174869del NG_008481.4:g.151651_151652del LRG_130:g.151651_151652del - Protein change
- Q1165fs, Q1203fs, Q1092fs, Q1102fs, Q1134fs, Q1152fs, Q1168fs, Q1211fs, Q1033fs, Q1067fs, Q1175fs, Q1193fs, Q910fs
- Other names
- -
- Canonical SPDI
- NC_000005.10:112839169:ACA:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
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
|
Jun 26, 2019 | RCV001567918.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 22, 2022 | RCV002460078.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 17, 2023 | RCV004564100.2 | |
|
APC-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Mar 7, 2024 | RCV004740244.1 |
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
(Jun 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001791691.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
Frameshift 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)
Frameshift 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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Dobbie 1996, De Rosa 2003, Kanter-Smoler 2008); This variant is associated with the following publications: (PMID: 31269945, 8730280, 18433509, 20685668, 20223039, 14961559, 23159591, 9067764, 7746201) (less)
|
|
|
Pathogenic
(Oct 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000552650.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1193Valfs*14) 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.Gln1193Valfs*14) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1651 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 (FAP) (PMID: 1843350, 7746201, 8730280, 9067764, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 411475). 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)
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002618056.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.3577_3578delCA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 3577 and … (more)
The c.3577_3578delCA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 3577 and 3578, causing a translational frameshift with a predicted alternate stop codon (p.Q1193Vfs*14). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1651 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This alteration has been detected in individuals with personal and family histories of familial adenomatous polyposis (FAP) (Kerr SE et al. J Mol Diagn 2013;15(1):31-43; Friedl W et al. Hered Cancer Clin Pract 2005;3(3):95-114; Dobbie Z et al. J. Med. Genet. 1996;33(4):274-80; Scarano MI et al. Hum. Mutat. 1997;9(2):191-3; Gerdehsang PS et al. Intl. Journal Hum. Genet. 2017;14(4):145-150). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004044686.2
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.
|
|
|
Pathogenic
(Mar 07, 2024)
|
no assertion criteria provided
Method: clinical testing
|
APC-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005343471.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The APC c.3577_3578delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln1193Valfs*14). This variant was reported in individuals with adenomatous polyposis … (more)
The APC c.3577_3578delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln1193Valfs*14). This variant was reported in individuals with adenomatous polyposis coli (for example, Lagarde et al. 2010. PubMed ID: 20685668; reported as somatic mosaicism in Kim B et al 2019. PubMed ID: 31269945; Dobbie Z et al 1996. PubMed ID: 8730280; Kerr SE et al 2012. PubMed ID: 23159591). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is also classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/411475/). Based on above information, this variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Gln1193Valfs*14) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1651 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 (FAP) (PMID: 1843350, 7746201, 8730280, 9067764, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 411475). 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.
Comment:
The c.3577_3578delCA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 3577 and 3578, causing a translational frameshift with a predicted alternate stop codon (p.Q1193Vfs*14). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1651 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This alteration has been detected in individuals with personal and family histories of familial adenomatous polyposis (FAP) (Kerr SE et al. J Mol Diagn 2013;15(1):31-43; Friedl W et al. Hered Cancer Clin Pract 2005;3(3):95-114; Dobbie Z et al. J. Med. Genet. 1996;33(4):274-80; Scarano MI et al. Hum. Mutat. 1997;9(2):191-3; Gerdehsang PS et al. Intl. Journal Hum. Genet. 2017;14(4):145-150). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
The APC c.3577_3578delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln1193Valfs*14). This variant was reported in individuals with adenomatous polyposis coli (for example, Lagarde et al. 2010. PubMed ID: 20685668; reported as somatic mosaicism in Kim B et al 2019. PubMed ID: 31269945; Dobbie Z et al 1996. PubMed ID: 8730280; Kerr SE et al 2012. PubMed ID: 23159591). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is also classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/411475/). Based on above information, this variant is interpreted as pathogenic.
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:
Frameshift 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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Dobbie 1996, De Rosa 2003, Kanter-Smoler 2008); This variant is associated with the following publications: (PMID: 31269945, 8730280, 18433509, 20685668, 20223039, 14961559, 23159591, 9067764, 7746201)
Comment:
This sequence change creates a premature translational stop signal (p.Gln1193Valfs*14) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1651 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 (FAP) (PMID: 1843350, 7746201, 8730280, 9067764, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 411475). 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.
Comment:
The c.3577_3578delCA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 3577 and 3578, causing a translational frameshift with a predicted alternate stop codon (p.Q1193Vfs*14). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1651 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This alteration has been detected in individuals with personal and family histories of familial adenomatous polyposis (FAP) (Kerr SE et al. J Mol Diagn 2013;15(1):31-43; Friedl W et al. Hered Cancer Clin Pract 2005;3(3):95-114; Dobbie Z et al. J. Med. Genet. 1996;33(4):274-80; Scarano MI et al. Hum. Mutat. 1997;9(2):191-3; Gerdehsang PS et al. Intl. Journal Hum. Genet. 2017;14(4):145-150). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
The APC c.3577_3578delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln1193Valfs*14). This variant was reported in individuals with adenomatous polyposis coli (for example, Lagarde et al. 2010. PubMed ID: 20685668; reported as somatic mosaicism in Kim B et al 2019. PubMed ID: 31269945; Dobbie Z et al 1996. PubMed ID: 8730280; Kerr SE et al 2012. PubMed ID: 23159591). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is also classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/411475/). Based on above information, this variant is interpreted as pathogenic.
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 |
| APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. | Kerr SE | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23159591 |
| 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 |
| 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 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 |
| Three novel germline mutations in the adenomatous polyposis coli gene. | Scarano MI | Human mutation | 1997 | PMID: 9067764 |
| Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene. | Dobbie Z | Journal of medical genetics | 1996 | PMID: 8730280 |
| Genetic counselling and gene mutation analysis in familial adenomatous polyposis in Western Australia. | Walpole IR | The Medical journal of Australia | 1995 | PMID: 7746201 |
| 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 |
| Physiological mechanisms of pregnancy recognition in ruminants. | Bazer FW | Journal of reproduction and fertility. Supplement | 1991 | PMID: 1843350 |
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Text-mined citations for rs1060503326 ...
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.