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 D116Efs*18 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 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) | 0.0 | 15 bp |
| Donor Loss (DL) | 0.0 | 145 bp |
| Acceptor Gain (AG) | 0.0 | 389 bp |
| Donor Gain (DG) | 0.0 | 23 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule/finding for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: c.348del causes a frameshift (p.D116Efs*18) resulting in loss of PTEN function, in a gene where loss-of-function is a known mechanism and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for null variants.
PS1 (Not Applied)
According to VCEP guidelines, the rule/finding for PS1 is: "Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: there is no previously established pathogenic variant resulting in the same amino acid change at codon 116. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule/finding for PS2 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." The evidence for this variant shows: no de novo status or parental confirmation data are available. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule/finding 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." The evidence for this variant shows: functional studies demonstrate that the D116Efs*18 truncation abolishes PTEN phosphatase function, leading to oncogenic activation. Therefore, this criterion is applied at Strong strength because PTEN-specific functional data meet PS3 requirements.
PS4 (Not Applied)
According to VCEP guidelines, the rule/finding for PS4 is: "Strong Strength: Probands with specificity score 4–15.5 OR increased prevalence in affected vs. controls." The evidence for this variant shows: no case-control data or specificity scores are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule/finding for PM1 is: "Moderate Strength: Located in a mutational hotspot or critical functional domain (residues 90–94, 123–130, 166–168)." The evidence for this variant shows: codon 116 is outside these defined catalytic motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule/finding for PM2 is: "Supporting Strength: Absent in population databases or present at <0.001% allele frequency." The evidence for this variant shows: it is not found in gnomAD or other large population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM3 is: "Moderate Strength: Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: PTEN is haploinsufficient and no trans observations apply. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule/finding for PM4 is: "Moderate Strength: Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: c.348del is a frameshift leading to premature termination, not an in-frame change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule/finding for PM5 is: "Moderate Strength: Different missense change at an amino acid where a pathogenic missense has been seen." The evidence for this variant shows: it is a frameshift, not a missense at the same residue. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule/finding for PM6 is: "Very Strong Strength: Two proven or four assumed de novo observations or one proven + two assumed de novo." The evidence for this variant shows: no unconfirmed de novo observations are reported. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule/finding for PP1 is: "Supporting Strength: Co-segregation with disease in multiple affected family members (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/finding for PP2 is: "Supporting Strength: Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule/finding for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: in silico tools (SpliceAI, REVEL) predict no splicing or missense impact but this is a truncating variant. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP4 is: "Supporting Strength: Patient’s phenotype is highly specific for a disorder with a single genetic etiology." The evidence for this variant shows: no detailed phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP5 is: "Supporting Strength: Reputable source classifies variant as pathogenic without primary evidence." The evidence for this variant shows: no ClinVar or other reputable source record. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule/finding for BA1 is: "Stand Alone Strength: Allele frequency >0.056%." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule/finding for BS1 is: "Strong Strength: Allele frequency 0.0043%–0.056%." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule/finding for BS2 is: "Strong Strength: Observed homozygous in healthy individual(s)." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule/finding for BS3 is: "Strong Strength: Well-established functional studies show no damaging effect." 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/finding 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/finding for BP1 is: "Supporting Strength: Missense variant in gene where only truncating variants 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/finding for BP2 is: "Supporting Strength: Observed in trans with a pathogenic PTEN variant." The evidence for this variant shows: no trans observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines, the rule/finding for BP3 is: "Supporting Strength: In-frame indels in a repetitive region." The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule/finding for BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: computational data are not relevant for truncating mechanism. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP6 is: "Supporting Strength: Variant classified as benign by a reputable source without evidence." The evidence for this variant shows: no such classification exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule/finding for BP7 is: "Supporting Strength: Synonymous or intronic variant with no splicing impact." The evidence for this variant shows: it is a frameshift in coding region. Therefore, this criterion is not applied.