ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.883A>G (p.Ser295Gly)
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.
Uncertain significance(5); Benign(2); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.883A>G (p.Ser295Gly)
Variation ID: 135729 Accession: VCV000135729.61
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112815543 (GRCh38) [ NCBI UCSC ] 5: 112151240 (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 Dec 19, 2017 Aug 4, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.883A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Ser295Gly missense NM_001127510.3:c.883A>G NP_001120982.1:p.Ser295Gly missense NM_001127511.3:c.829A>G NP_001120983.2:p.Ser277Gly missense NM_001354895.2:c.883A>G NP_001341824.1:p.Ser295Gly missense NM_001354896.2:c.883A>G NP_001341825.1:p.Ser295Gly missense NM_001354897.2:c.913A>G NP_001341826.1:p.Ser305Gly missense NM_001354898.2:c.808A>G NP_001341827.1:p.Ser270Gly missense NM_001354899.2:c.799A>G NP_001341828.1:p.Ser267Gly missense NM_001354900.2:c.706A>G NP_001341829.1:p.Ser236Gly missense NM_001354901.2:c.706A>G NP_001341830.1:p.Ser236Gly missense NM_001354902.2:c.913A>G NP_001341831.1:p.Ser305Gly missense NM_001354903.2:c.883A>G NP_001341832.1:p.Ser295Gly missense NM_001354904.2:c.808A>G NP_001341833.1:p.Ser270Gly missense NM_001354905.2:c.706A>G NP_001341834.1:p.Ser236Gly missense NM_001354906.2:c.34A>G NP_001341835.1:p.Ser12Gly missense NC_000005.10:g.112815543A>G NC_000005.9:g.112151240A>G NG_008481.4:g.128023A>G LRG_130:g.128023A>G - Protein change
- S295G, S277G, S267G, S305G, S12G, S236G, S270G
- Other names
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- Canonical SPDI
- NC_000005.10:112815542:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00002
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 | ||
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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
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. |
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APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14956 | 15094 |
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
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 15, 2023 | RCV000213708.19 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jul 31, 2024 | RCV001192830.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 1, 2023 | RCV001778740.12 | |
Benign (1) |
criteria provided, single submitter
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Jan 1, 2022 | RCV003153407.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 6, 2024 | RCV004567057.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Aug 02, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361209.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: APC c.883A>G (p.Ser295Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: APC c.883A>G (p.Ser295Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.883A>G has been reported in the literature in individuals in the lieterature affected with gastric cancer (Ge_2017) and schizophrenia (Yang_2017). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. 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) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Feb 01, 2023)
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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: SCV002015522.3
First in ClinVar: Nov 20, 2021 Last updated: Nov 11, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer in The Cancer Genome Atlas … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer in The Cancer Genome Atlas (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 28195569, 32980694, 29684080) (less)
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Benign
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ovarian cancer
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Accession: SCV003843495.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
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Uncertain significance
(Feb 15, 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: SCV000905876.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with glycine at codon 295 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with glycine at codon 295 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer in the literature (PMID: 33193653). This variant has been identified in 6/282508 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Mar 06, 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:
unknown
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Baylor Genetics
Accession: SCV005052090.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Jan 24, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166071.8
First in ClinVar: Jun 16, 2014 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 295 of the APC protein (p.Ser295Gly). … (more)
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 295 of the APC protein (p.Ser295Gly). This variant is present in population databases (rs587780611, gnomAD 0.02%). This missense change has been observed in individual(s) with biliary tract cancer (PMID: 36243179). ClinVar contains an entry for this variant (Variation ID: 135729). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Benign
(Oct 26, 2022)
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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: SCV000273263.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550574.5
First in ClinVar: Jul 30, 2022 Last updated: Aug 04, 2024 |
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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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Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. | Okawa Y | Journal of hepatology | 2023 | PMID: 36243179 |
New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients. | Djursby M | Frontiers in genetics | 2020 | PMID: 33193653 |
Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
Genomic alterations in advanced gastric cancer endoscopic biopsy samples using targeted next-generation sequencing. | Ge S | American journal of cancer research | 2017 | PMID: 28744403 |
Rare damaging variants in DNA repair and cell cycle pathways are associated with hippocampal and cognitive dysfunction: a combined genetic imaging study in first-episode treatment-naive patients with schizophrenia. | Yang Z | Translational psychiatry | 2017 | PMID: 28195569 |
Text-mined citations for rs587780611 ...
HelpRecord last updated Oct 13, 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.