Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.5 | Alternative | 8719 nt | 1032–2243 |
| NM_000314.4 | Alternative | 5572 nt | 1032–2243 |
| NM_000314.3 | Alternative | 3416 nt | 1032–2243 |
| NM_000314.6 | Alternative | 8718 nt | 1032–2243 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN D115Efs*2 variant is a truncating mutation that results in the loss of PTEN phosphatase function. Functional studies have demonstrated that such truncating mutations lead to an inability to negatively regulate the PI3K/AKT pathway, contributing to oncogenic activity. Additionally, expression of PTEN truncation mutations in mouse embryonic fibroblasts has shown increased genome fragility due to impaired chromosomal centromere association. These findings support a damaging effect of the PTEN D115Efs*2 variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 393 bp |
| Donor Loss (DL) | 0.0 | 149 bp |
| Acceptor Gain (AG) | 0.02 | -107 bp |
| Donor Gain (DG) | 0.0 | 51 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows a frameshift duplication (NM_000314.8:c.344dupA) resulting in a premature stop (D115Efs*2) predicted to cause loss of function. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where loss of function is a known mechanism of disease.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant...". The evidence for this variant shows a frameshift alteration, not the same amino acid change as any known pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations... Strong Strength: De novo (both maternity and paternity confirmed)...". There are no data regarding de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.". The evidence for this variant shows multiple functional studies demonstrating that truncating PTEN variants abolish phosphatase activity, disrupt regulation of the PI3K/AKT pathway, and increase genomic instability. Therefore, this criterion is applied at Strong strength because well-established functional assays support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Probands with specificity score 4-15.5 OR prevalence significantly increased in affected vs controls...". No case-level or cohort data are available for this variant. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: Moderate Located in a mutational hot spot and/or critical and well-established functional domain: residues 90-94, 123-130, 166-168.". The variant affects codon 115, which is outside the defined critical functional domains. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Supporting Absent in population Databases present at <0.001% allele frequency in gnomAD or another large sequenced population.". The evidence for this variant shows it is not present in gnomAD (MAF=0). Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Moderate Strength: Moderate Detected in trans with a pathogenic variant in recessive disorders...". PTEN-related conditions are autosomal dominant and there is no evidence of a trans configuration with another pathogenic PTEN variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants...". The variant is a frameshift leading to a premature stop, not an in-frame change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before...". The variant is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations... Strong Strength: Two probands with presumed de novo occurrence... Moderate Strength: Assumed de novo without confirmation...". No data on assumed de novo occurrence are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting Strength: Supporting Co-segregation with disease in multiple affected family members...". No family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.". The variant is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product...". In silico predictions, including SpliceAI (max score 0.02), do not support a deleterious effect. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Supporting Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.". No clinical phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Supporting Reputable source recently reports variant as pathogenic...". There is no ClinVar or other reputable report. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.056%.". The allele frequency for this variant is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.0043% up to 0.056%.". The allele frequency for this variant is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual...". No homozygous observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.". Functional studies for this variant demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Strong Lack of segregation in affected members of two or more families.". No segregation data exist. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease.". This variant is truncating, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant...". No such observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: Supporting In-frame deletions/insertions in a repetitive region without a known function.". The variant is a frameshift, not in-frame. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product.". Computational evidence does not indicate benign effect for a truncating variant. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Supporting Variant found in a case with an alternate molecular basis for disease.". No alternate molecular basis is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: Supporting Reputable source reports variant as benign.". No such report exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Supporting A synonymous or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.". This variant is not synonymous or intronic. Therefore, this criterion is not applied.