Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| 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 |
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis sequence change creates a premature translational stop signal (p.Pro248Leufs*8) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN P248Lfs*8 variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that such truncating mutations are oncogenic, leading to increased genome fragility and an inability to associate with chromosomal centromeres.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.06 | -52 bp |
| Donor Loss (DL) | 0.0 | 60 bp |
| Acceptor Gain (AG) | 0.01 | -163 bp |
| Donor Gain (DG) | 0.01 | -127 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." The evidence for this variant shows: it is a frameshift (c.743del; P248Lfs*8) predicted to result in loss of function in a gene where LOF is a known disease mechanism and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because the PTEN PVS1 decision tree supports applying PVS1 to truncating variants upstream of the final exon.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant." The evidence for this variant shows: this is a frameshift, not a missense change matching a known pathogenic amino acid substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Strong: De novo (confirmed) occurrence in a patient with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3 (Strong)
According to PTEN pre-processing, the finding for PS3 is: "The PTEN P248Lfs*8 variant is a truncating mutation that results in the loss of PTEN phosphatase function... Functional studies have shown that such truncating mutations are oncogenic." The evidence for this variant shows: well-established in vitro/in vivo studies confirm loss of function and oncogenic effect. Therefore, this criterion is applied at Strong strength because functional studies demonstrate a damaging effect per VCEP PS3 definition.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong: Prevalence in affected individuals significantly increased versus controls or specificity score 4–15.5." 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 is: "Moderate: Located in a mutational hotspot or critical domain (residues 90–94, 123–130, 166–168)." The evidence for this variant shows: position 248 is outside defined hotspots and domains. Therefore, this criterion is not applied.
PM2 (Supporting)
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: MAF=0% in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population datasets.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Moderate: 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: "Moderate: Protein length changes due to in-frame indels in non-repeat region or stop-loss variants." The evidence for this variant shows: it is a frameshift leading to premature termination, covered by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate: Novel missense change at a residue with a different known pathogenic missense variant." The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Strong: Assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting: Co-segregation with disease in family (3–4 meioses)." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene with low benign missense variation." 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: "Supporting: Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: SpliceAI score of 0.06 indicates minimal splicing impact, and computational tools are not informative for a frameshift. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Supporting: Patient’s phenotype highly specific for gene." The evidence for this variant shows: no detailed phenotype data provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar lists this variant as Pathogenic by two clinical laboratories. Therefore, this criterion is applied at Supporting strength because of reputable external assertions.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Allele frequency >0.056% in gnomAD." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: Allele frequency 0.0043–0.056% in gnomAD." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: Observed homozygous in healthy individuals." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: 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: "Strong: Lack of segregation in affected members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting: Missense variant in gene where only truncating variants cause disease." The evidence for this variant shows: it is a truncating variant, the opposite of a benign missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting: Observed in trans or cis with other pathogenic variants." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame indels in repetitive regions." The evidence for this variant shows: it is a frameshift, not an in-frame indel in a repeat. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Computational evidence suggests no impact." The evidence for this variant shows: this is a frameshift, and computational tools are not informative. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Supporting: Variant found in a case with an alternate molecular basis." The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Reputable source reports variant as benign without evidence." The evidence for this variant shows: no benign assertions exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Silent or intronic variant with no splicing impact." The evidence for this variant shows: it is a frameshift, not a silent or intronic variant. Therefore, this criterion is not applied.