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 D371Efs*45 variant is a truncating mutation that results in a loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that expression of PTEN truncation mutations in mouse embryonic fibroblasts is oncogenic and increases genome fragility due to impaired chromosomal centromere association. This evidence supports a damaging effect of the variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -79 bp |
| Donor Loss (DL) | 0.0 | 94 bp |
| Acceptor Gain (AG) | 0.0 | -85 bp |
| Donor Gain (DG) | 0.01 | -8 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease'. The evidence for this variant shows: NM_000314.8:c.1113del is a frameshift predicted to result in a truncated PTEN protein (D371Efs*45) upstream of the last exon. Therefore, this criterion is applied at Very Strong strength because it is a null variant in PTEN, where loss of function is a known disease mechanism.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: '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: no previously established pathogenic variant at this amino acid. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history'. The evidence for this variant shows: no parental testing or de novo confirmation data available. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: '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 studies demonstrate that the D371Efs*45 truncation abolishes PTEN phosphatase activity and is oncogenic in cellular models. Therefore, this criterion is applied at Strong strength.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Prevalence of the variant in affected individuals significantly increased compared with the prevalence in controls OR probands with specificity score ≥4'. The evidence for this variant shows: no case series or case-control data available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168)'. The evidence for this variant shows: residue D371 is outside the defined hotspot regions. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Absent in population Databases or present at <0.00001 allele frequency in gnomAD'. The evidence for this variant shows: not found in gnomAD or other large population databases. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant'. The evidence for this variant shows: no data on trans configuration with another PTEN variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is a frameshift resulting in truncation, not an in-frame change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before'. The evidence for this variant shows: it is not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members (3–4 meioses for Supporting)'. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: '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 evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect'. The evidence for this variant shows: in silico tools assess splicing only and show minimal impact; frameshift itself predicts LOF. Computational predictions for missense/splicing are not applicable. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no detailed phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without available evidence'. The evidence for this variant shows: no such assertion found in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'gnomAD Filtering allele frequency >0.00056'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'gnomAD Filtering allele frequency from 0.000043 up to 0.00056'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Observed in the homozygous state in a healthy individual'. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect'. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: 'Lack of segregation in affected members of two or more families'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in gene where only truncating variants cause disease'. The evidence for this variant shows: it is truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Observed in cis/trans with other pathogenic variants'. The evidence for this variant shows: no allelic configuration data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without a known function'. The evidence for this variant shows: it is a frameshift, not an in-frame event. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: computational tools assess splicing only; frameshift automatically predicts LOF; computational benign evidence is not relevant. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no alternate diagnosis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without evidence'. The evidence for this variant shows: no such assertions found. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Synonymous or intronic variant with no impact on splicing'. The evidence for this variant shows: it is a frameshift, not synonymous/intronic. Therefore, this criterion is not applied.