PTEN c.448G>T, p.Glu150Ter
NM_000314.8:c.448G>T
COSMIC ID: COSM921099
Pathogenic
This nonsense variant results in a loss of function in PTEN, a known disease mechanism, is absent from population databases, supported by functional studies (Moderate) and reputable pathogenic assertions (Supporting), meeting PVS1 (Very Strong) plus PS3, PM2, and PP5 to classify as Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.448G>T
Protein Change
E150*
Location
Exon 5
(Exon 5 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM921099
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.448G>T
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant has been observed in an individual with clinical features of PTEN hamartoma tumor syndrome (PMID: 21194675). ClinVar contains an entry for this variant (Variation ID: 189489). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu150*) in the PTEN gene. It is expected to result in an absent or disrupted protein product.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
The PTEN E150* variant is a truncating mutation that results in a premature stop codon, leading to the production of a truncated PTEN protein. Functional studies indicate that this truncation results in a loss of PTEN phosphatase activity, as demonstrated by reduced activity in a yeast assay. Additionally, expression of similar truncating mutations in mouse embryonic fibroblasts has shown oncogenic properties, including increased genome fragility and impaired regulation of the PI3K/AKT pathway. These findings support the conclusion that the PTEN E150* variant has a damaging effect on protein function.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 9.98
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Use PTEN PVS1 decision tree.' The evidence for this variant shows: a truncating (nonsense) variant in PTEN where loss of function is a known mechanism and it is not located in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant meets the PTEN PVS1 decision tree for null variants.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: no different nucleotide change resulting in the same E150* has been reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations.' The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: 'PS3_Moderate evidence added based on high-confidence functional score (-3.9486) < threshold (-1.11).' The evidence for this variant shows: phosphatase activity score of -3.9486 in a yeast assay indicating damaging effect. Therefore, this criterion is applied at Moderate strength because the functional score meets the PTEN PS3 threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong prevalence in affected individuals or specificity score 4-15.5.' The evidence for this variant shows: no case or specificity score data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate Located in a mutational hot spot or critical domain including residues 90-94, 123-130, 166-168.' The evidence for this variant shows: E150 is outside defined PTEN hotspot residues. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Absent in population Databases present at <0.00001 allele frequency in gnomAD.' The evidence for this variant shows: not observed in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Moderate Detected in trans with a pathogenic variant for recessive disorders.' The evidence for this variant shows: PTEN-related disease is autosomal dominant, no trans data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate Protein length changes due to in-frame insertions/deletions or stop-loss variants.' The evidence for this variant shows: it is a nonsense, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate Missense change at an amino acid residue where a different missense change is pathogenic.' The evidence for this variant shows: it is a nonsense variant, not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations.' The evidence for this variant shows: no assumed de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting Missense variant in gene with low rate of benign missense variation.' The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Multiple lines of computational evidence support a deleterious effect.' The evidence for this variant shows: it is a nonsense variant and computational predictors are not relevant. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Reputable source reports variant as pathogenic but evidence not available for independent evaluation.' The evidence for this variant shows: ClinVar lists this variant as Pathogenic by three clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone gnomAD Filtering allele frequency >0.00056.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong gnomAD Filtering allele frequency 0.000043–0.00056.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong Observed in homozygous state in healthy individuals.' The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Functional studies show no damaging effect.' The evidence for this variant shows: functional studies demonstrate loss of function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong Lack of segregation in affected members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting Missense variant in a gene where only truncating variants cause disease.' The evidence for this variant shows: it is truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Supporting Observed in trans with a pathogenic variant for recessive disorders.' The evidence for this variant shows: no trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP3 is: 'Supporting In-frame indels in repetitive regions.' The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: computational tools are not relevant to a nonsense variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting Reputable source reports variant as benign.' The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting Synonymous or intronic variant with no splicing impact.' The evidence for this variant shows: it is nonsense. Therefore, this criterion is not applied.