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
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN E150Gfs*27 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have demonstrated that such truncating mutations are oncogenic, increasing genome fragility and disrupting chromosomal centromere association.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 288 bp |
| Donor Loss (DL) | 0.0 | -78 bp |
| Acceptor Gain (AG) | 0.0 | -6 bp |
| Donor Gain (DG) | 0.0 | 44 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the PVS1 rule is: "Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: c.449_456del (E150Gfs*27) is a frameshift/truncating variant in PTEN, a gene where loss‐of‐function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant meets PVS1 criteria per the PTEN VCEP decision tree.
PS1 (Not Applied)
According to VCEP guidelines, the PS1 rule is: "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, where in silico models predict impact equal to or greater than the known pathogenic variant." The evidence for this variant shows: no previously established pathogenic variant with the same amino acid change or splicing effect. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the PS2 rule is: "Strong 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 de novo data available. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the PS3 rule is: "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: functional studies demonstrate that E150Gfs*27 abolishes PTEN phosphatase activity, disrupts PI3K/AKT regulation, and is oncogenic. Therefore, this criterion is applied at Strong strength because strong functional evidence supports a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the PS4 rule is: "Strong Probands with specificity score 4-15.5 OR prevalence significantly increased in affected vs. controls." The evidence for this variant shows: no case reports or specificity scores available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the PM1 rule is: "Moderate Located in a mutational hot spot and/or critical functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: variant is a frameshift outside defined catalytic motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the PM2 rule is: "Supporting Absent in population Databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows: MAF = 0% in gnomAD; variant not found in population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent in controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the PM3 rule is: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: no phasing or allelic configuration data. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the PM4 rule is: "Moderate Protein length changes due to in-frame indels in non-repeat region or stop-loss variants." The evidence for this variant shows: this is a frameshift LOF variant, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the PM5 rule is: "Moderate Missense change at a residue where another pathogenic missense change has been seen." The evidence for this variant shows: this is not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the PM6 rule is: "Moderate Assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the PP1 rule is: "Supporting Co‐segregation in multiple affected family members (3-4 meioses)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the PP2 rule is: "Supporting Missense variant in a gene with low benign missense variation where missense is common disease mechanism." The evidence for this variant shows: variant is frameshift, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the PP3 rule is: "Supporting Multiple lines of computational evidence support a deleterious effect (REVEL > 0.7 or SpliceAI/VarSeak concordance)." The evidence for this variant shows: minimal predicted splicing impact (SpliceAI = 0.01) and no deleterious in silico predictions. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the PP4 rule is: "Supporting Patient’s phenotype or family history highly specific for a disease with 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 PP5 rule is: "Supporting Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the BA1 rule is: "Stand Alone gnomAD Filtering allele frequency >0.00056." The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the BS1 rule is: "Strong gnomAD Filtering allele frequency 0.000043–0.00056." The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the BS2 rule is: "Strong Observed homozygous in healthy individual." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the BS3 rule is: "Strong Well-established studies show no damaging effect." The evidence for this variant shows: studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the BS4 rule is: "Strong Lack of segregation in 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 BP1 rule is: "Supporting Missense in gene where only LOF causes disease." The evidence for this variant shows: variant is LOF, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the BP2 rule is: "Supporting Observed in trans with pathogenic variant or ≥3 cis observations." The evidence for this variant shows: no phasing or cis/trans data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the BP3 rule is: "Supporting In-frame indel in repetitive region without functional effect." The evidence for this variant shows: variant is frameshift, not in a repeat region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the BP4 rule is: "Supporting Computational evidence suggests no impact (REVEL <0.5 or SpliceAI/VarSeak concordance)." The evidence for this variant shows: minimal splicing impact but overall LOF mechanism dominates. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the BP5 rule is: "Supporting Variant found in a case with an alternate molecular basis for disease." 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 BP6 rule is: "Supporting Reputable source reports variant as benign." The evidence for this variant shows: no benign reports in databases. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the BP7 rule is: "Supporting Synonymous or intronic variant with no splice impact." The evidence for this variant shows: it is not synonymous/intronic. Therefore, this criterion is not applied.