ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.830C>T (p.Thr277Ile)
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.830C>T (p.Thr277Ile)
Variation ID: 184277 Accession: VCV000184277.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 87960922 (GRCh38) [ NCBI UCSC ] 10: 89720679 (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 24, 2015 May 1, 2024 Jun 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000314.8:c.830C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000305.3:p.Thr277Ile missense NM_001304717.5:c.1349C>T NP_001291646.4:p.Thr450Ile missense NM_001304718.2:c.239C>T NP_001291647.1:p.Thr80Ile missense NC_000010.11:g.87960922C>T NC_000010.10:g.89720679C>T NG_007466.2:g.102484C>T LRG_311:g.102484C>T LRG_311t1:c.830C>T - Protein change
- T277I, T80I, T450I
- Other names
- NM_000314.8(PTEN):c.830C>T
- p.Thr277Ile
- Canonical SPDI
- NC_000010.11:87960921:C: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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PTEN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3035 | 3528 |
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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Uncertain significance (1) |
criteria provided, single submitter
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May 3, 2023 | RCV000163498.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 14, 2020 | RCV001269397.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2020 | RCV001559615.2 | |
Pathogenic (2) |
reviewed by expert panel
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Jun 14, 2023 | RCV003454396.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV003493469.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Pathogenic
(Jun 14, 2023)
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reviewed by expert panel
Method: curation
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PTEN hamartoma tumor syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Clingen PTEN Variant Curation Expert Panel, Clingen
Accession: SCV004183295.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
NM_000314.8(PTEN):c.830C>T (p.Thr277Ile) variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG … (more)
NM_000314.8(PTEN):c.830C>T (p.Thr277Ile) variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (PMID:25549896 and internal laboratory contributor). PS3_M: Phosphatase activity = -1.11 per Mighell et al. 2018, PMID: 29706350. PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score=0.988) PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 25549896). (less)
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Likely pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Macrocephaly-autism syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004244350.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PS4_MOD,PS2_MOD,PM5,PM2_SUP,PP3,PP2
Clinical Features:
Macrocephaly (present) , Motor delay (present)
Sex: female
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Pathogenic
(Nov 06, 2022)
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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: SCV004295320.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Thr277 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28263967; Invitae). … (more)
This variant disrupts the p.Thr277 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28263967; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt PTEN protein function. ClinVar contains an entry for this variant (Variation ID: 184277). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 25549896). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 277 of the PTEN protein (p.Thr277Ile). (less)
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Uncertain significance
(May 03, 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: SCV000214056.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.T277I variant (also known as c.830C>T), located in coding exon 8 of the PTEN gene, results from a C to T substitution at nucleotide … (more)
The p.T277I variant (also known as c.830C>T), located in coding exon 8 of the PTEN gene, results from a C to T substitution at nucleotide position 830. The threonine at codon 277 is replaced by isoleucine, an amino acid with some similar properties. This variant was reported as de novo (unconfirmed parentage) in a female child followed from birth to age 4 who presented with macrocephaly followed by patent ductus arteriosus, nevus flammeus of the philtrum suggestive of Megalencephaly-Capillary Malformation syndrome, overgrowth, widespread capillary malformations, enlarged cerebral ventricles identified by MRI and speech support was needed for learning disabilities (Busa T et al. Eur J Paediatr Neurol, 2015 Mar;19:188-92). In addition, RNA studies was performed for this variant and no abnormal splicing was reported to be associated (Wai HA et al. Genet Med, 2020 Jun;22:1005-1014). However, in a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was reported to be in the hypomorphic range of functionally abnormal (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Feb 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome
Affected status: yes
Allele origin:
germline
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Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV001449168.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Comment:
ClinGen PTEN Expert Panel Specification v2 used for classification. Data included in classification: UK family #1: Paediatric phenotype specificity score 3 (extreme macrocephaly + 2 … (more)
ClinGen PTEN Expert Panel Specification v2 used for classification. Data included in classification: UK family #1: Paediatric phenotype specificity score 3 (extreme macrocephaly + 2 (autism/dev delay)=5. Literature case #1 Busa et al, 2015 (PMID: 25549896): Paediatric phenotype specificity score 3 (extreme macrocephaly) + 2 (enlarged cerebral ventricles)=5. 2 probands with paediatric specificity score of 5=2 points (PS4_mod). The variant was absent from the gnomAD population (141,456 individuals) (PM2_mod). Literature case #1: de novo in proband (PM6_mod). ExAC constraint score: 3.71, gnomAD constraint score: 3.49 i.e. low benign missense rate (PP2_sup). Data not included in classification: In silico: Revel score 0.988. The variant is in protein domains: Tensin phosphatase, C2 domain, Bifunctional phosphatidylinositol trisphosphate phosphatase/dual specificity phosphatase PTEN C2 domain. (less)
Number of individuals with the variant: 1
Geographic origin: United Kingdom
Testing laboratory: UK Molecular Diagnostic Labs
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Pathogenic
(Jul 27, 2020)
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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: SCV001781885.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Published functional studies demonstrate reduced lipid phosphatase activity (Mighell 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors … (more)
Published functional studies demonstrate reduced lipid phosphatase activity (Mighell 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32123317, 25549896, 29706350) (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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Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. | Wai HA | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32123317 |
A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. | Mighell TL | American journal of human genetics | 2018 | PMID: 29706350 |
Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. | Yang JM | Oncogene | 2017 | PMID: 28263967 |
Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome. | Busa T | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2015 | PMID: 25549896 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a777d351-791d-4ae1-8feb-2a6403a3fe1f | - | - | - | - |
Text-mined citations for rs398123329 ...
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.