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 Y177Ffs*6 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that such truncating mutations in PTEN are oncogenic, increasing genome fragility due to the failure of PTEN to associate with chromosomal centromeres. 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) | 0.01 | -36 bp |
| Donor Loss (DL) | 0.01 | 105 bp |
| Acceptor Gain (AG) | 0.01 | 8 bp |
| Donor Gain (DG) | 0.0 | -21 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 at Very Strong strength is: "Use PTEN PVS1 decision tree". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift resulting in a premature stop codon, representing a null variant in PTEN, where loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP-defined truncating variant rule.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 at Strong strength is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change...". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift variant, not a missense change matching a known pathogenic amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 at Very Strong strength is: "Two proven OR four assumed OR one proven + two assumed de novo observations..." and at Strong strength: "De novo (both maternity and paternity confirmed) observation...". The evidence for this variant shows: No de novo occurrence data are provided. Therefore, this criterion is not applied.
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 at Strong strength 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: Functional studies demonstrate that Y177Ffs*6 abolishes PTEN phosphatase activity and leads to oncogenic effects. Therefore, this criterion is applied at Strong strength because the variant has well-established damaging functional evidence.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 at Strong strength is: "Probands with specificity score 4-15.5 or increased prevalence in cases vs controls". The evidence for this variant shows: No case-control or specificity score data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 at Moderate strength 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: Position 177 is outside the specified hotspot domains. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 at Supporting strength is: "Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.". The evidence for this variant shows: It is not found in gnomAD (MAF=0). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For autosomal recessive disorders, detected in trans with a pathogenic variant.". The evidence for this variant shows: No data on phase or cis/trans occurrence with another PTEN variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 at Moderate strength is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift variant, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 at Very Strong strength is: "Two proven OR four assumed OR one proven + two assumed de novo observations without confirmation of paternity.". The evidence for this variant shows: No presumed de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 at Supporting strength is: "Co-segregation with disease in multiple affected family members, with 3-4 meioses observed.". The evidence for this variant shows: No segregation data provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 at Supporting strength is: "Missense variant in a gene that has a low rate of benign missense variation and where missense is a common mechanism of disease.". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 at Supporting strength is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.". The evidence for this variant shows: In silico tools show minimal splicing impact (SpliceAI score 0.01) and no otherwise predictive deleterious computational data. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 at Supporting strength 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 or family history data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 at Supporting strength is: "Reputable source reports variant as pathogenic without available evidence.". The evidence for this variant shows: Not found in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 at Stand Alone strength is: "gnomAD Filtering allele frequency >0.00056 (0.056%).". The evidence for this variant shows: Allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 at Strong strength is: "gnomAD Filtering allele frequency from 0.000043 to 0.00056.". The evidence for this variant shows: Allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 at Strong strength is: "Observed in the homozygous state in a healthy individual.". The evidence for this variant shows: No homozygous observations reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 at Strong strength is: "Well-established functional studies show no damaging effect on protein function.". 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 at Strong strength 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 at Supporting strength is: "Missense variant in a gene where only truncating variants are pathogenic.". The evidence for this variant shows: It is a truncating variant, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 at Supporting strength is: "Observed in trans with a pathogenic PTEN variant.". The evidence for this variant shows: No phase data with another variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 at Supporting strength is: "In-frame indels in a repetitive region without known function.". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift, not an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 at Supporting strength is: "Multiple lines of computational evidence suggest no impact.". The evidence for this variant shows: Computational evidence indicates null variant with functional impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 at Supporting strength is: "Variant found in a case with an alternate molecular basis for disease.". The evidence for this variant shows: No such case data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 at Supporting strength is: "Reputable source reports variant as benign without evidence.". The evidence for this variant shows: No reputable source reports this variant. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 at Supporting strength is: "Synonymous or intronic variant with no impact on splicing predictions.". The evidence for this variant shows: It is a frameshift variant. Therefore, this criterion is not applied.