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 R233Gfs*8 variant is a truncating mutation that results in the loss of PTEN phosphatase function. This loss of function impairs the negative regulation of the PI3K/AKT pathway, contributing to oncogenic activity. Functional studies have shown that PTEN truncation mutations lead to increased genome fragility and an inability to associate with chromosomal centromeres, supporting a damaging effect of this variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.07 | -4 bp |
| Donor Loss (DL) | 0.0 | -156 bp |
| Acceptor Gain (AG) | 0.02 | -202 bp |
| Donor Gain (DG) | 0.01 | -79 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: it is a frameshift (R233Gfs*8) resulting in a premature stop codon in PTEN, a gene where loss-of-function is a known mechanism of disease, and the variant is not located in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP decision tree for null variants.
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, where in silico models predict impact equal to or greater than the known pathogenic variant. Modification Type: Disease-specific". The evidence for this variant shows: there is no previously established pathogenic variant resulting in the same amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Strong Strength: Strong De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. Modification Type: None". The evidence for this variant shows: no information on de novo occurrence with parental confirmation is available. 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. Modification Type: Disease-specific". The evidence for this variant shows: functional studies demonstrate that R233Gfs*8 abolishes PTEN phosphatase activity, impairs PI3K/AKT regulation, increases genome fragility, and disrupts chromosomal centromere association. Therefore, this criterion is applied at Strong strength because well-established assays support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Strong Probands with specificity score 4-15.5 OR significant increase in prevalence in affected vs controls. Modification Type: Strength". The evidence for this variant shows: no case-level data or specificity scores are available. 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. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3). Modification Type: Disease-specific". The evidence for this variant shows: position R233 is outside the defined catalytic motifs. 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 <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. Modification Type: Disease-specific". The evidence for this variant shows: it is absent from 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 standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PTEN-related disease is autosomal dominant and there are no reports of this variant in trans with another pathogenic allele. 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. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif. Modification Type: Disease-specific". The evidence for this variant shows: it is a frameshift leading to truncation, 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. BLOSUM62 score requirement applies. Modification Type: Disease-specific". The evidence for this variant shows: it 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: "Moderate Strength: Moderate Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history. Modification Type: None". The evidence for this variant shows: no information on presumed de novo occurrence is 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, with 3 or 4 meioses observed. Modification Type: Disease-specific". The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP 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 evidence for this variant shows: it 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 (e.g., REVEL >0.7 for missense)." The evidence for this variant shows: it is a truncating frameshift and computational tools are not applicable. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Phenotype specificity for the disease with a single genetic etiology." The evidence for this variant shows: no detailed phenotype or specificity score is 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: it is not present in ClinVar or other reputable databases. 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 >0.00056 (0.056%). Modification Type: Disease-specific". 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 is: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056 (0.0043–0.056%). Modification Type: Disease-specific". 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: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual..." The evidence for this variant shows: no homozygous observations in healthy individuals. 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. Modification Type: Disease-specific". The evidence for this variant shows: functional studies show 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. Modification Type: Disease-specific". The evidence for this variant shows: no segregation data indicating lack of segregation. 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." The evidence for this variant shows: it is a truncating variant. 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 OR at least three observations in cis..." 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 Strength: Supporting In-frame deletions/insertions in a repetitive region without a known functional domain." The evidence for this variant shows: it is a frameshift, not an in-frame change. 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. Splicing variants: Concordance of SpliceAI and VarSeak; Missense: REVEL <0.5." The evidence for this variant shows: it is a truncating variant, and computational splicing predictions are not applicable to frameshifts. 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." 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 is: "Supporting Strength: Supporting Reputable source reports variant as benign without available evidence." The evidence for this variant shows: no reputable benign classification 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 with no predicted splice impact." The evidence for this variant shows: it is a frameshift, not a synonymous/intronic variant. Therefore, this criterion is not applied.