ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.716T>C (p.Met239Thr)
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_000314.8(PTEN):c.716T>C (p.Met239Thr)
Variation ID: 826884 Accession: VCV000826884.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 87957934 (GRCh38) [ NCBI UCSC ] 10: 89717691 (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 Mar 16, 2020 May 1, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000314.8:c.716T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000305.3:p.Met239Thr missense NM_001304717.5:c.1235T>C NP_001291646.4:p.Met412Thr missense NM_001304718.2:c.125T>C NP_001291647.1:p.Met42Thr missense NC_000010.11:g.87957934T>C NC_000010.10:g.89717691T>C NG_007466.2:g.99496T>C LRG_311:g.99496T>C LRG_311t1:c.716T>C - Protein change
- M412T, M239T, M42T
- Other names
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- Canonical SPDI
- NC_000010.11:87957933: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
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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PTEN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3036 | 3528 |
Conditions - Germline
Condition
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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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Dec 20, 2021 | RCV001026114.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 17, 2023 | RCV001547857.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV002465824.3 |
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
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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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Uncertain significance
(Oct 14, 2022)
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criteria provided, single submitter
Method: curation
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PTEN hamartoma tumor syndrome
Affected status: yes
Allele origin:
germline
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Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV002760193.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
Data included in classification: Segregation across 4 meiosis observed (PP1_mod) Present at <0.001% allele frequency in gnomAD (Observed in 1/125723 individuals in gnomAD v2.1.1) (PM2_sup) … (more)
Data included in classification: Segregation across 4 meiosis observed (PP1_mod) Present at <0.001% allele frequency in gnomAD (Observed in 1/125723 individuals in gnomAD v2.1.1) (PM2_sup) REVEL: 0.719 (PP3_sup) PTEN is constrained with a significance Z score (more than 3.09) (PP2_sup) Data not included in classification: Phenotypic features for the proband and their family members (none reach the minimum Cleveland Score threshold for application of PS4) (less)
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Uncertain significance
(May 17, 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: SCV001767657.2
First in ClinVar: Aug 07, 2021 Last updated: May 27, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); A published … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); A published functional study demonstrates wildtype-like phosphatase activity (Mighell et al., 2018); This variant is associated with the following publications: (PMID: 28424201, 25669429, 32003824, 18626510, 28475857, 29706350) (less)
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Uncertain significance
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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PTEN hamartoma tumor syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003439550.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the PTEN protein (p.Met239Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the PTEN protein (p.Met239Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 28475857, 32003824). ClinVar contains an entry for this variant (Variation ID: 826884). 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 PTEN protein function with a negative predictive value of 80%. 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 20, 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: SCV001188433.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.M239T variant (also known as c.716T>C), located in coding exon 7 of the PTEN gene, results from a T to C substitution at nucleotide … (more)
The p.M239T variant (also known as c.716T>C), located in coding exon 7 of the PTEN gene, results from a T to C substitution at nucleotide position 716. The methionine at codon 239 is replaced by threonine, an amino acid with similar properties. This variant has been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). This variant was also reported in a child with macrocephaly and mild intellectual disability as well as in his affected father, although the family's cancer history (if any) was not reported (Tatton-Brown K et al. Am. J. Hum. Genet., 2017 May;100:725-736). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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Copy Number Variation and Clinical Outcomes in Patients With Germline PTEN Mutations. | Yehia L | JAMA network open | 2020 | PMID: 32003824 |
A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. | Mighell TL | American journal of human genetics | 2018 | PMID: 29706350 |
Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. | Tatton-Brown K | American journal of human genetics | 2017 | PMID: 28475857 |
KLLN epigenotype-phenotype associations in Cowden syndrome. | Nizialek EA | European journal of human genetics : EJHG | 2015 | PMID: 25669429 |
Text-mined citations for rs786204871 ...
HelpRecord last updated May 01, 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.