ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.220G>T (p.Glu74Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.220G>T (p.Glu74Ter)
Variation ID: 231074 Accession: VCV000231074.54
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112766410 (GRCh38) [ NCBI UCSC ] 5: 112102107 (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 Jan 7, 2017 Feb 20, 2024 Sep 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.220G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Glu74Ter nonsense NM_001127510.3:c.220G>T NP_001120982.1:p.Glu74Ter nonsense NM_001127511.3:c.250G>T NP_001120983.2:p.Glu84Ter nonsense NM_001354895.2:c.220G>T NP_001341824.1:p.Glu74Ter nonsense NM_001354896.2:c.220G>T NP_001341825.1:p.Glu74Ter nonsense NM_001354897.2:c.250G>T NP_001341826.1:p.Glu84Ter nonsense NM_001354898.2:c.145G>T NP_001341827.1:p.Glu49Ter nonsense NM_001354899.2:c.220G>T NP_001341828.1:p.Glu74Ter nonsense NM_001354900.2:c.43G>T NP_001341829.1:p.Glu15Ter nonsense NM_001354901.2:c.43G>T NP_001341830.1:p.Glu15Ter nonsense NM_001354902.2:c.250G>T NP_001341831.1:p.Glu84Ter nonsense NM_001354903.2:c.220G>T NP_001341832.1:p.Glu74Ter nonsense NM_001354904.2:c.145G>T NP_001341833.1:p.Glu49Ter nonsense NM_001354905.2:c.43G>T NP_001341834.1:p.Glu15Ter nonsense NM_001354906.2:c.-816G>T 5 prime UTR NC_000005.10:g.112766410G>T NC_000005.9:g.112102107G>T NG_008481.4:g.78890G>T LRG_130:g.78890G>T - Protein change
- E74*, E84*, E49*, E15*
- Other names
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- Canonical SPDI
- NC_000005.10:112766409:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
14000 | 14134 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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May 30, 2021 | RCV000215333.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 8, 2016 | RCV000254875.10 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV000501460.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 25, 2023 | RCV002228955.17 |
Submissions - Germline
Classification
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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
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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
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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
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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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Likely pathogenic
(Nov 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322197.7
First in ClinVar: Oct 09, 2016 Last updated: Jan 07, 2017 |
Comment:
This variant is denoted APC c.220G>T at the cDNA level. Located in the last nucleotide of exon 3, it destroys a natural splice donor site … (more)
This variant is denoted APC c.220G>T at the cDNA level. Located in the last nucleotide of exon 3, it destroys a natural splice donor site and causes abnormal splicing. RNA analyses by Schwarzova et al. (2013) demonstrated that this variant results in skipping of exon 3, referred to as exon 2 using alternate nomenclature, as well as a second alternate transcript with skipping of exons 3 and 4 (also known as exons 2 and 3). These alternate transcripts may result in the production of some functional protein by using an alternate downstream AUG start codon at position 184. APC proteins produced from this alternate start codon have been shown to have normal cellular localization and ability to regulate B-catenin levels, which may explain the attenuated phenotype seen in some patients with 5' truncating APC variants (Heppner Goss 2002). APC c.220G>T has been seen in at least one individual with colorectal cancer who was reported to have attenuated familial adenomatous polyposis (AFAP), though the number of polyps was not described (Stekrova 2007). Although the nucleotide substitution is predicted to result in the change of a Glutamic Acid to a premature stop codon, and is called Glu74Ter in the literature, we are only using the nucleotide nomenclature to refer to the variant since it is not clear if any truncated protein from the premature stop codon is translated or if the observed abnormal splicing mitigates the effect of the premature stop codon. APC c.220G>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Based on currently available evidence, we consider APC c.220G>T to be a likely pathogenic variant. (less)
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Pathogenic
(May 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000274815.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.220G>T pathogenic mutation (also known as p.E74*), located in coding exon 2 of the APC gene, results from a G to T substitution at … (more)
The c.220G>T pathogenic mutation (also known as p.E74*), located in coding exon 2 of the APC gene, results from a G to T substitution at nucleotide position 220. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. This mutation has been reported in one or more individuals with attenuated FAP (Ambry internal data; Stekrova Jet al. BMC Med Genet. 2007 Apr 5;8:16). This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing and RNA studies have shown that this alteration results in a transcript with out-of-frame skipping of coding exon 2 (Ambry internal data; Schwarzová L et al. Fam. Cancer 2013 Mar; 12(1):35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, alterations that result in premature termination in coding exon 2 are associated with an attenuated phenotype and may have reduced penetrance compared to classic familial adenomatous polyposis syndrome. Clinical correlation is advised. (less)
Number of individuals with the variant: 1
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Pathogenic
(Apr 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004044525.2
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.
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Pathogenic
(Sep 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000552521.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 231074). Studies have shown that this premature translational stop signal results in skipping of exon 3 … (more)
ClinVar contains an entry for this variant (Variation ID: 231074). Studies have shown that this premature translational stop signal results in skipping of exon 3 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with attenuated adenomatous polyposis (PMID: 17411426). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu74*) in the APC gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591020.3 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Comment:
The APC p.Glu74X variant was identified in a family with an attenuated form of familial adenomatous polyposis (Schwarzova 2012). The p.Glu74X variant was also identified … (more)
The APC p.Glu74X variant was identified in a family with an attenuated form of familial adenomatous polyposis (Schwarzova 2012). The p.Glu74X variant was also identified in HGMD, “InSiGHT Colon Cancer Database” and LOVD. This alteration would typically be predicted to result in a truncated or absent protein and loss of function; however, one study has demonstrated that for APC mutations closer to the 5’ terminus, an internal ribosome entry site is utilized to initiate translation at codon 184, resulting in a partially functional N-terminally truncated protein, which results in an attenuated phenotype (Heppner Goss 2002). The p.Glu74X variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In a functional study by Schwarzova (2012), mRNA analysis showed that this variant created an aberrant splicing product which skipped exon 2 and could lead to expression of a truncated protein 48 amino acids long, or that would partly be subject to nonsense mediated decay. However, the authors of this study found another alternatively spliced APC transcript in all mRNA samples from control colon mucosa; this transcript was also found in the proband’s mRNA isolated from blood, but not in control blood samples. The authors suggest that the presence of this transcript in the patient’s blood may lead to the attenuated phenotype shown in the positive proband’s family. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel mutations of the APC gene and genetic consequences of splicing mutations in the Czech FAP families. | Schwarzová L | Familial cancer | 2013 | PMID: 22987206 |
Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects. | Stekrova J | BMC medical genetics | 2007 | PMID: 17411426 |
Text-mined citations for rs876658941 ...
HelpRecord last updated Apr 15, 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.