ClinVar Genomic variation as it relates to human health
NM_001127511.3(APC):c.-191T>C
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_001127511.3(APC):c.-191T>C
Variation ID: 243005 Accession: VCV000243005.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112707527 (GRCh38) [ NCBI UCSC ] 5: 112043224 (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 Jul 16, 2016 Apr 15, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001127511.3:c.-191T>C 5 prime UTR NM_001354895.2:c.-374T>C 5 prime UTR NM_001354897.2:c.-191T>C 5 prime UTR NM_001354902.2:c.-191T>C 5 prime UTR NM_001407446.1:c.-191T>C 5 prime UTR NM_001407447.1:c.-374T>C 5 prime UTR NM_001407448.1:c.-141T>C 5 prime UTR NM_001407450.1:c.-141T>C 5 prime UTR NM_001407452.1:c.-374T>C 5 prime UTR NM_001407453.1:c.-165T>C 5 prime UTR NM_001407456.1:c.-374T>C 5 prime UTR NM_001407457.1:c.-141T>C 5 prime UTR NM_001407458.1:c.-141T>C 5 prime UTR NM_001407460.1:c.-374T>C 5 prime UTR NM_001407469.1:c.-374T>C 5 prime UTR NM_001407470.1:c.-1409T>C 5 prime UTR NM_001407472.1:c.-1409T>C 5 prime UTR NR_176365.1:n.30T>C non-coding transcript variant NR_176366.1:n.30T>C non-coding transcript variant NC_000005.10:g.112707527T>C NC_000005.9:g.112043224T>C NG_008481.4:g.20007T>C NG_173817.1:g.150T>C LRG_130:g.20007T>C LRG_130t3:c.-374T>C - Protein change
- Other names
- -191T-C
- Canonical SPDI
- NC_000005.10:112707526:T:C
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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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14000 | 14134 | |
LOC129994371 | - | - | - | GRCh38 | - | 109 |
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. |
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not provided (1) |
criteria provided, single submitter
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- | RCV000234996.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 6, 2023 | RCV001013699.12 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 23, 2021 | RCV001290975.11 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV001559545.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 19, 2024 | RCV003743685.1 |
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
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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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Pathogenic
(Feb 05, 2021)
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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: SCV001781791.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Describes a nucleotide substitution 191 base pairs upstream of the ATG translational start site of the APC promoter 1B region Published functional studies demonstrate a … (more)
Describes a nucleotide substitution 191 base pairs upstream of the ATG translational start site of the APC promoter 1B region Published functional studies demonstrate a damaging effect: decreased YY1 binding and significantly reduced transcriptional activity compared to wild-type (Li 2016) Also defined as APC c.-30417T>C using an alternate reference sequence (NM_000038.5) This variant is associated with the following publications: (PMID: 32895333, 27087319, 27343414, 29968043) (less)
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Pathogenic
(Jan 10, 2023)
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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: SCV001174319.4
First in ClinVar: Mar 16, 2020 Last updated: Apr 15, 2023 |
Comment:
The c.-191T>C pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the APC gene. This pathogenic mutation results from a T to … (more)
The c.-191T>C pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the APC gene. This pathogenic mutation results from a T to C substitution 191 bases upstream from the first translated codon. This alteration has been described in five families with clinically-confirmed gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). In all five of these families, the mutation was detected in the germline of all available affected individuals, and it was not detected in available unaffected individuals, showing strong segregation with disease (Repak R et al. Gastrointest. Endosc. 2016 Oct;84:718-25; Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). The alteration impacts a highly-conserved nucleotide within the YY1 binding motif of APC promoter 1B, and authors demonstrated disrupted protein binding associated with c.-191T>C. Furthermore, luciferase assay results showed significantly reduced promoter activity for this variant compared to wild type (Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). This nucleotide position is highly conserved on limited sequence alignment. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004025013.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Pathogenic
(Jan 19, 2024)
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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: SCV000768181.8
First in ClinVar: Jul 16, 2016 Last updated: Feb 20, 2024 |
Comment:
This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. This … (more)
This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 27087319, 27343414). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-191T>C. ClinVar contains an entry for this variant (Variation ID: 243005). Studies have shown that this variant alters APC gene expression (PMID: 27087319). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821304.8
First in ClinVar: Jan 21, 2023 Last updated: Apr 15, 2024 |
Comment:
APC: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Dec 06, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004361310.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant is located in the 5' untranslated region of the APC gene. This variant is reported as c.-191T>C on an alternative transcript NM_001127511.3. A … (more)
This variant is located in the 5' untranslated region of the APC gene. This variant is reported as c.-191T>C on an alternative transcript NM_001127511.3. A functional study has shown this variant results in significantly decreased transcriptional activity compared to wild type protein in colorectal cancer and gastric cancer cell lines (PMID: 27087319). This variant has been reported in individuals and families affected with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 2996804, 31409086). It has been shown that this variant segregates with GAPPS syndrome in numerous families (PMID: 2996804, 31409086). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Feb 23, 2021)
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no assertion criteria provided
Method: literature only
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GASTRIC ADENOCARCINOMA AND PROXIMAL POLYPOSIS OF THE STOMACH
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000292336.3
First in ClinVar: Jul 16, 2016 Last updated: Feb 28, 2021 |
Comment on evidence:
In 4 families (2, 4, 5, and 6) with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS; 619182), 1 of which was the US … (more)
In 4 families (2, 4, 5, and 6) with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS; 619182), 1 of which was the US family originally described by Worthley et al. (2012) as family 2, Li et al. (2016) identified heterozygosity for a c.-191T-C transition (c.-191T-C, NM_001127511) in a YY1 binding motif of the APC promoter 1B that segregated with disease in all 4 families and was not found in 344 germline samples from an in-house WGS cancer project or in the 1000 Genomes Project database. By EMSA, Li et al. (2016) demonstrated that the c.-191T-C mutation disrupts binding to the promoter 1B region in both AGS and RKO cells. In luciferase reporter assays, constructs with c.-191T-C showed significantly decreased activity compared to wildtype. In a father and 3 daughters from a 3-generation Czech family with GAPPS, Repak et al. (2016) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. DNA analysis was not reported for the paternal grandmother who also had proximal gastric polyposis and died of gastric cancer at age 49 years. In a 38-year-old Austrian woman with GAPPS, Beer et al. (2017) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. DNA was unavailable from her father, who died of gastric cancer at age 57 years. In 24 individuals from 8 Czech families with GAPPS, Foretova et al. (2019) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. Of the 24 mutation carriers, 20 had massive gastric polyposis; in addition, 1 female carrier had incipient polyposis at age 58 years, 2 female carriers did not have polyposis of the stomach at ages 31 and 65, and a 92-year-old asymptomatic male carrier did not undergo gastroscopy due to his advanced age. In affected members of 2 multiplex Japanese families with GAPPS, Kanemitsu et al. (2021) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Familial adenomatous polyposis 1
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV001423254.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 02-21-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 02-21-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Family history of cancer (present)
Indication for testing: Presymptomatic
Age: 50-59 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-02-21
Testing laboratory interpretation: Pathogenic
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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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Two Asian families with gastric adenocarcinoma and proximal polyposis of the stomach successfully treated via laparoscopic total gastrectomy. | Kanemitsu K | Clinical journal of gastroenterology | 2021 | PMID: 33242120 |
GAPPS - Gastric Adenocarcinoma and Proximal Polyposis of the Stomach Syndrome in 8 Families Tested at Masaryk Memorial Cancer Institute - Prevention and Prophylactic Gastrectomies. | Foretová L | Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti | 2019 | PMID: 31409086 |
First report of an Asian family with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) revealed with the germline mutation of the APC exon 1B promoter region. | Mitsui Y | Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association | 2018 | PMID: 29968043 |
Neoplastic Lesions of Gastric Adenocarcinoma and Proximal Polyposis Syndrome (GAPPS) Are Gastric Phenotype. | de Boer WB | The American journal of surgical pathology | 2018 | PMID: 29112017 |
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) - a rare recently described gastric polyposis syndrome - report of a case. | Beer A | Zeitschrift fur Gastroenterologie | 2017 | PMID: 29141268 |
The first European family with gastric adenocarcinoma and proximal polyposis of the stomach: case report and review of the literature. | Repak R | Gastrointestinal endoscopy | 2016 | PMID: 27343414 |
Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. | Li J | American journal of human genetics | 2016 | PMID: 27087319 |
Familial fundic gland polyposis with gastric cancer. | Yanaru-Fujisawa R | Gut | 2012 | PMID: 22027476 |
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. | Worthley DL | Gut | 2012 | PMID: 21813476 |
The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat. | Manning AS | Circulation research | 1985 | PMID: 2996804 |
Text-mined citations for rs879253783 ...
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.