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: 236589). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 1338764, 16134147, 20223039, 20685668). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1114*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1730 amino acid(s) of the APC protein.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.3340C>T (p.Arg1114Ter)
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.
(13)
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
13
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.
Likely oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_000038.6(APC):c.3340C>T (p.Arg1114Ter)
Variation ID: 236589 Accession: VCV000236589.38
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q22.2 5: 112838934 (GRCh38) [ NCBI UCSC ] 5: 112174631 (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 Mar 8, 2017 May 1, 2024 May 8, 2023 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.3340C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Arg1114Ter nonsense NM_001127510.3:c.3340C>T NP_001120982.1:p.Arg1114Ter nonsense NM_001127511.3:c.3286C>T NP_001120983.2:p.Arg1096Ter nonsense NM_001354895.2:c.3340C>T NP_001341824.1:p.Arg1114Ter nonsense NM_001354896.2:c.3394C>T NP_001341825.1:p.Arg1132Ter nonsense NM_001354897.2:c.3370C>T NP_001341826.1:p.Arg1124Ter nonsense NM_001354898.2:c.3265C>T NP_001341827.1:p.Arg1089Ter nonsense NM_001354899.2:c.3256C>T NP_001341828.1:p.Arg1086Ter nonsense NM_001354900.2:c.3217C>T NP_001341829.1:p.Arg1073Ter nonsense NM_001354901.2:c.3163C>T NP_001341830.1:p.Arg1055Ter nonsense NM_001354902.2:c.3067C>T NP_001341831.1:p.Arg1023Ter nonsense NM_001354903.2:c.3037C>T NP_001341832.1:p.Arg1013Ter nonsense NM_001354904.2:c.2962C>T NP_001341833.1:p.Arg988Ter nonsense NM_001354905.2:c.2860C>T NP_001341834.1:p.Arg954Ter nonsense NM_001354906.2:c.2491C>T NP_001341835.1:p.Arg831Ter nonsense NC_000005.10:g.112838934C>T NC_000005.9:g.112174631C>T NG_008481.4:g.151414C>T LRG_130:g.151414C>T - Protein change
- R1096*, R1114*, R1013*, R1023*, R1073*, R1086*, R1089*, R1124*, R1132*, R954*, R988*, R831*, R1055*
- Other names
- -
- Canonical SPDI
- NC_000005.10:112838933:C:T
-
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 |
14962 | 15100 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000424284.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000434269.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 27, 2019 | RCV000501152.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 7, 2022 | RCV000491362.15 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001353812.10 | |
| Pathogenic (2) |
no assertion criteria provided
|
- | RCV001723814.11 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 8, 2023 | RCV002516270.13 |
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
(Apr 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000282738.9
First in ClinVar: Jul 01, 2016 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: 236589). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 1338764, 16134147, 20223039, 20685668). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1114*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1730 amino acid(s) of the APC protein. (less)
|
|
|
Pathogenic
(Nov 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000579776.7
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The p.R1114* pathogenic mutation (also known as c.3340C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at … (more)
The p.R1114* pathogenic mutation (also known as c.3340C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3340. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been reported in multiple families with familial adenomatous polyposis (FAP) (Nagase H et al. Hum. Mutat. 1992;1:467-73; Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Schwarzová L et al. Fam. Cancer, 2013 Mar;12:35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)
|
|
|
Pathogenic
(Feb 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361155.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: APC c.3340C>T (p.Arg1114X) 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.3340C>T (p.Arg1114X) 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 (c.3927_3931delAAAGA, p.Glu1309fsX4; c.4393_4394dupAG, p.Ser1465fsX9; c.5582_5585delCTTT, p.Ser1861fsX1). The variant was absent in 245192 control chromosomes. c.3340C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Ficari_2000, Friedl_2005, Kanter-Smoler_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001347727.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with polyposis and familial adenomatous polyposis (PMID: 1338764, 20685668, 20223039, 16134147). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004043969.2
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.
|
|
|
Pathogenic
(Apr 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206684.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504997.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504998.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Carcinoma of colon
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591137.3 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Arg1114X variant was identified in 17 of 3924 proband chromosomes (frequency: 0.004) from individuals or families with familial adenomatous polyposis or colorectal cancer, and … (more)
The p.Arg1114X variant was identified in 17 of 3924 proband chromosomes (frequency: 0.004) from individuals or families with familial adenomatous polyposis or colorectal cancer, and was not identified in 158 control chromosomes from healthy individuals (Aceto 2005; Ficari 2000; Friedl 2005; Kanter-Smoler 2008; Liu 2007; Nagase 1992; Rivers 2010; van der Luijt 1997; Vandrovcova 2004). The p.Arg1114X variant was also identified in dbSNP (ID: rs121913331), HGMD, UMD (25X), “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and the COSMIC database. This variant is in the last exon and truncating variants in this region of the RNA may sometimes be subject to nonsense mediated RNA decay; this cannot be predicted. However, the p.Arg1114X variant leads to a premature stop codon at position 1114, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In addition, Liu (2007) identified this variant in tumour tissues and predict it as a hot spot mutation with higher rate of cancer metastasis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956320.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001976074.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Likely pathogenic
(Jul 21, 2023)
|
no assertion criteria provided
Method: research
|
Familial adenomatous polyposis 1
Affected status: yes
Allele origin:
germline
|
deCODE genetics, Amgen
Accession: SCV004022213.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000038.6:c.3340C>T (chr5:112838934) in APC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar … (more)
The variant NM_000038.6:c.3340C>T (chr5:112838934) in APC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 1
Ethnicity/Population group: Icelandic
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial adenomatous polyposis 1
Affected status: yes
Allele origin:
unknown
|
Genomics And Bioinformatics Analysis Resource, Columbia University
Accession: SCV004024149.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023
Comment:
Heterozygous
|
|
|
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Comment:
Comment:
The p.R1114* pathogenic mutation (also known as c.3340C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3340. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been reported in multiple families with familial adenomatous polyposis (FAP) (Nagase H et al. Hum. Mutat. 1992;1:467-73; Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Schwarzová L et al. Fam. Cancer, 2013 Mar;12:35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Comment:
Variant summary: APC c.3340C>T (p.Arg1114X) 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 (c.3927_3931delAAAGA, p.Glu1309fsX4; c.4393_4394dupAG, p.Ser1465fsX9; c.5582_5585delCTTT, p.Ser1861fsX1). The variant was absent in 245192 control chromosomes. c.3340C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Ficari_2000, Friedl_2005, Kanter-Smoler_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with polyposis and familial adenomatous polyposis (PMID: 1338764, 20685668, 20223039, 16134147). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The p.Arg1114X variant was identified in 17 of 3924 proband chromosomes (frequency: 0.004) from individuals or families with familial adenomatous polyposis or colorectal cancer, and was not identified in 158 control chromosomes from healthy individuals (Aceto 2005; Ficari 2000; Friedl 2005; Kanter-Smoler 2008; Liu 2007; Nagase 1992; Rivers 2010; van der Luijt 1997; Vandrovcova 2004). The p.Arg1114X variant was also identified in dbSNP (ID: rs121913331), HGMD, UMD (25X), “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and the COSMIC database. This variant is in the last exon and truncating variants in this region of the RNA may sometimes be subject to nonsense mediated RNA decay; this cannot be predicted. However, the p.Arg1114X variant leads to a premature stop codon at position 1114, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In addition, Liu (2007) identified this variant in tumour tissues and predict it as a hot spot mutation with higher rate of cancer metastasis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The variant NM_000038.6:c.3340C>T (chr5:112838934) in APC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely 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:
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: 236589). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 1338764, 16134147, 20223039, 20685668). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1114*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1730 amino acid(s) of the APC protein.
Comment:
The p.R1114* pathogenic mutation (also known as c.3340C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3340. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been reported in multiple families with familial adenomatous polyposis (FAP) (Nagase H et al. Hum. Mutat. 1992;1:467-73; Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Schwarzová L et al. Fam. Cancer, 2013 Mar;12:35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Comment:
Variant summary: APC c.3340C>T (p.Arg1114X) 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 (c.3927_3931delAAAGA, p.Glu1309fsX4; c.4393_4394dupAG, p.Ser1465fsX9; c.5582_5585delCTTT, p.Ser1861fsX1). The variant was absent in 245192 control chromosomes. c.3340C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Ficari_2000, Friedl_2005, Kanter-Smoler_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with polyposis and familial adenomatous polyposis (PMID: 1338764, 20685668, 20223039, 16134147). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The p.Arg1114X variant was identified in 17 of 3924 proband chromosomes (frequency: 0.004) from individuals or families with familial adenomatous polyposis or colorectal cancer, and was not identified in 158 control chromosomes from healthy individuals (Aceto 2005; Ficari 2000; Friedl 2005; Kanter-Smoler 2008; Liu 2007; Nagase 1992; Rivers 2010; van der Luijt 1997; Vandrovcova 2004). The p.Arg1114X variant was also identified in dbSNP (ID: rs121913331), HGMD, UMD (25X), “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and the COSMIC database. This variant is in the last exon and truncating variants in this region of the RNA may sometimes be subject to nonsense mediated RNA decay; this cannot be predicted. However, the p.Arg1114X variant leads to a premature stop codon at position 1114, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In addition, Liu (2007) identified this variant in tumour tissues and predict it as a hot spot mutation with higher rate of cancer metastasis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The variant NM_000038.6:c.3340C>T (chr5:112838934) in APC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely 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 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Targeted sequencing of cancer-related genes in colorectal cancer using next-generation sequencing. | Han SW | PloS one | 2013 | PMID: 23700467 |
| 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 |
| Molecular genetic analysis of 103 sporadic colorectal tumours in Czech patients. | Vasovcak P | PloS one | 2011 | PMID: 21901162 |
| Clinical and genetic characterization of classical forms of familial adenomatous polyposis: a Spanish population study. | Rivera B | Annals of oncology : official journal of the European Society for Medical Oncology | 2011 | PMID: 20924072 |
| 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 |
| Somatic mutations affect key pathways in lung adenocarcinoma. | Ding L | Nature | 2008 | PMID: 18948947 |
| Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families. | Kanter-Smoler G | BMC medicine | 2008 | PMID: 18433509 |
| 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 |
| Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli. | Aceto G | Human mutation | 2005 | PMID: 16134147 |
| EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. | Wen Y | Nature cell biology | 2004 | PMID: 15311282 |
| APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis. | Ficari F | British journal of cancer | 2000 | PMID: 10646887 |
| Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. | Brensinger JD | Gut | 1998 | PMID: 9824584 |
| Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. | Miyaki M | Cancer research | 1994 | PMID: 8187091 |
| 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 |
| [The effect of occlusion time in the measurement of compliance and resistance of the respiratory system using passive expiration in infants]. | Steinbrugger B | Pneumologie (Stuttgart, Germany) | 1990 | PMID: 2281069 |
| http://docm.genome.wustl.edu/variants/ENST00000257430:c.3340C>T | - | - | - | - |
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Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Likely oncogenic
criteria provided, single submitter
|
Jul 31, 2024 | RCV004668862.1 |
Submissions - Somatic
|
Oncogenicity
Help
The submitted oncogenicity 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Likely oncogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094077.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 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 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: 236589). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 1338764, 16134147, 20223039, 20685668). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1114*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1730 amino acid(s) of the APC protein.
Comment:
The p.R1114* pathogenic mutation (also known as c.3340C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3340. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been reported in multiple families with familial adenomatous polyposis (FAP) (Nagase H et al. Hum. Mutat. 1992;1:467-73; Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Schwarzová L et al. Fam. Cancer, 2013 Mar;12:35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Comment:
Variant summary: APC c.3340C>T (p.Arg1114X) 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 (c.3927_3931delAAAGA, p.Glu1309fsX4; c.4393_4394dupAG, p.Ser1465fsX9; c.5582_5585delCTTT, p.Ser1861fsX1). The variant was absent in 245192 control chromosomes. c.3340C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Ficari_2000, Friedl_2005, Kanter-Smoler_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with polyposis and familial adenomatous polyposis (PMID: 1338764, 20685668, 20223039, 16134147). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The p.Arg1114X variant was identified in 17 of 3924 proband chromosomes (frequency: 0.004) from individuals or families with familial adenomatous polyposis or colorectal cancer, and was not identified in 158 control chromosomes from healthy individuals (Aceto 2005; Ficari 2000; Friedl 2005; Kanter-Smoler 2008; Liu 2007; Nagase 1992; Rivers 2010; van der Luijt 1997; Vandrovcova 2004). The p.Arg1114X variant was also identified in dbSNP (ID: rs121913331), HGMD, UMD (25X), “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and the COSMIC database. This variant is in the last exon and truncating variants in this region of the RNA may sometimes be subject to nonsense mediated RNA decay; this cannot be predicted. However, the p.Arg1114X variant leads to a premature stop codon at position 1114, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In addition, Liu (2007) identified this variant in tumour tissues and predict it as a hot spot mutation with higher rate of cancer metastasis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The variant NM_000038.6:c.3340C>T (chr5:112838934) in APC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs121913331 ...
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 Oct 27, 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.