ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.5194A>G (p.Met1732Val)
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.5194A>G (p.Met1732Val)
Variation ID: 350414 Accession: VCV000350414.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112840788 (GRCh38) [ NCBI UCSC ] 5: 112176485 (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 6, 2016 May 1, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.5194A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Met1732Val missense NM_001127510.3:c.5194A>G NP_001120982.1:p.Met1732Val missense NM_001127511.3:c.5140A>G NP_001120983.2:p.Met1714Val missense NM_001354895.2:c.5194A>G NP_001341824.1:p.Met1732Val missense NM_001354896.2:c.5248A>G NP_001341825.1:p.Met1750Val missense NM_001354897.2:c.5224A>G NP_001341826.1:p.Met1742Val missense NM_001354898.2:c.5119A>G NP_001341827.1:p.Met1707Val missense NM_001354899.2:c.5110A>G NP_001341828.1:p.Met1704Val missense NM_001354900.2:c.5071A>G NP_001341829.1:p.Met1691Val missense NM_001354901.2:c.5017A>G NP_001341830.1:p.Met1673Val missense NM_001354902.2:c.4921A>G NP_001341831.1:p.Met1641Val missense NM_001354903.2:c.4891A>G NP_001341832.1:p.Met1631Val missense NM_001354904.2:c.4816A>G NP_001341833.1:p.Met1606Val missense NM_001354905.2:c.4714A>G NP_001341834.1:p.Met1572Val missense NM_001354906.2:c.4345A>G NP_001341835.1:p.Met1449Val missense NC_000005.10:g.112840788A>G NC_000005.9:g.112176485A>G NG_008481.4:g.153268A>G LRG_130:g.153268A>G - Protein change
- M1732V, M1714V, M1572V, M1606V, M1631V, M1742V, M1750V, M1641V, M1673V, M1449V, M1691V, M1704V, M1707V
- Other names
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- Canonical SPDI
- NC_000005.10:112840787: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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 |
14583 | 14717 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000338065.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 28, 2023 | RCV000482902.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 14, 2021 | RCV000779704.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 13, 2023 | RCV000573682.15 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001356468.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 18, 2023 | RCV003995883.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV003475934.2 |
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
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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APC-Associated Polyposis Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000452021.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Dec 14, 2017)
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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: SCV000564575.5
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
This variant is denoted APC c.5194A>G at the cDNA level, p.Met1732Val (M1732V) at the protein level, and results in the change of a Methionine to … (more)
This variant is denoted APC c.5194A>G at the cDNA level, p.Met1732Val (M1732V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Met1732Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Met1732Val is located in a beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Met1732Val is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Dec 04, 2017)
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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: SCV000916457.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: The APC c.5194A>G (p.Met1732Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant … (more)
Variant summary: The APC c.5194A>G (p.Met1732Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/245306 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. (less)
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Uncertain significance
(Oct 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002071924.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the APC gene demonstrated a sequence change, c.5194A>G, in exon 16 that results in an amino acid change, p.Met1732Val. This sequence … (more)
DNA sequence analysis of the APC gene demonstrated a sequence change, c.5194A>G, in exon 16 that results in an amino acid change, p.Met1732Val. This sequence change does not appear to have been previously described in individuals with APC-related disorders. This sequence change has been described in one south Asian individual and two non-Finnish European individuals in the gnomAD population database (dbSNP rs752065261). The p.Met1732Val change affects a highly conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met1732Val substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Met1732Val change remains unknown at this time. (less)
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Uncertain significance
(Aug 26, 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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Baylor Genetics
Accession: SCV004201322.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jun 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047215.3
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, … (more)
To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000012 (3/250548 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jun 08, 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: SCV001353229.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces methionine with valine at codon 1732 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces methionine with valine at codon 1732 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/250548 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
(Jan 25, 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: SCV000552648.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1732 of the APC protein (p.Met1732Val). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1732 of the APC protein (p.Met1732Val). This variant is present in population databases (rs752065261, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 350414). 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%. 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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Uncertain Significance
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Classic or attenuated familial adenomatous polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004838017.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces methionine with valine at codon 1732 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces methionine with valine at codon 1732 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250548 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)
Number of individuals with the variant: 6
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Uncertain significance
(Nov 13, 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: SCV000667401.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.M1732V variant (also known as c.5194A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide … (more)
The p.M1732V variant (also known as c.5194A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 5194. The methionine at codon 1732 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(-)
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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: SCV001551645.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The APC p.Met1732Val variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified … (more)
The APC p.Met1732Val variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs752065261) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, GeneDx, and three other submitters). The variant was identified in control databases in 3 of 245306 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 110926 chromosomes (freq: 0.00002) and South Asian in 1 of 30766 chromosomes (freq: 0.00003), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Met1732 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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
HelpThere are no citations for germline 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 rs752065261 ...
HelpRecord last updated May 12, 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.