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 Q298Rfs*2 variant is a truncating mutation that results in the loss of PTEN phosphatase function. This loss of function impairs the ability of PTEN to negatively regulate the PI3K/AKT pathway, contributing to oncogenic activity. Functional studies have shown that expression of PTEN truncation mutations in mouse embryonic fibroblasts leads to increased genome fragility and oncogenic potential due to the inability of PTEN to associate with chromosomal centromeres.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -44 bp |
| Donor Loss (DL) | 0.0 | 137 bp |
| Acceptor Gain (AG) | 0.0 | 205 bp |
| Donor Gain (DG) | 0.0 | 382 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 truncating frameshift (c.893_900delAAGAAATC; Q298Rfs*2) resulting in a premature stop codon and known loss of PTEN function, not in the last exon. Therefore, this criterion is applied at Very Strong strength because truncating variants in PTEN are established loss-of-function per the PTEN PVS1 decision tree.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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 prior pathogenic variant causing the same amino acid change at codon 298. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Strong Strength: 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 occurrence data. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." According to PTEN pre-processing, the finding for PS3 is: "The PTEN Q298Rfs*2 variant is a truncating mutation that results in the loss of PTEN phosphatase function... Functional studies have shown that expression of PTEN truncation mutations in mouse embryonic fibroblasts leads to increased genome fragility and oncogenic potential." The evidence for this variant shows well-established functional studies demonstrating loss of PTEN activity and increased oncogenic potential. Therefore, this criterion is applied at Strong strength because functional data support damaging effect per PTEN-specific PS3.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Probands with specificity score 4-15.5 OR the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls." The evidence for this variant shows no case-control or proband specificity data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: 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)." The evidence for this variant shows it affects codon 298, outside PTEN catalytic motifs. 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 (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 controls per VCEP PM2.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant in recessive disorders." The evidence for this variant shows no data on occurrence in trans with another PTEN variant and PTEN-related disease is autosomal dominant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants..." The evidence for this variant shows a frameshift 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: 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 a frameshift, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Moderate Strength: Assumed de novo, but without confirmation of paternity and maternity..." The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting Strength: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed." The evidence for this variant shows no 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 frameshift, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect on the gene or gene product...REVEL score >0.7 for missense or concordance for splicing." The evidence for this variant shows minimal predicted splicing impact (SpliceAI score 0.01) and no missense context. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows no phenotype data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic or likely pathogenic without shared evidence." The evidence for this variant shows it is not found in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows MAF=0% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows MAF=0% in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Observed in the homozygous state in a healthy or PHTS-unaffected individual..." 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 Strength: Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows damaging functional impact. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: 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 a gene for which primarily truncating variants are pathogenic." The evidence for this variant shows it is truncating, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: 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: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows a frameshift, not in-frame. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact on gene or gene product...REVEL scores <0.5 or splicing concordance." The evidence for this variant shows minimal predicted splicing impact but variant type is truncating, so computational evidence is not relevant. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows no alternate molecular diagnosis. 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 source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: A synonymous or intronic variant at or beyond +7/-21 with no predicted impact on splicing." The evidence for this variant shows it is a frameshift, not synonymous or intronic. Therefore, this criterion is not applied.