Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
| 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
OpenFor these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant has not been reported in the literature in individuals with PTEN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu43*) in the PTEN gene. It is expected to result in an absent or disrupted protein product.
"This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories)."
COSMIC Somatic Evidence
OpenFunctional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.34 | -54 bp |
| Donor Loss (DL) | 0.53 | 37 bp |
| Acceptor Gain (AG) | 0.0 | 103 bp |
| Donor Gain (DG) | 0.0 | 135 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: NM_000314.8:c.127G>T is a nonsense change (p.Glu43*) in PTEN, a gene where loss of function is a known disease mechanism and the variant does not occur in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for a canonical null variant leading to LOF.
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...". The evidence for this variant shows: p.Glu43* is not identical to any previously established pathogenic amino acid change at this residue nor is it a recapitulation of a known splice variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations...". The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3 (Moderate)
According to PTEN Pre-processing, the finding for PS3 is: "PS3_Moderate evidence added based on high-confidence functional score (-3.5729) < threshold (-1.11)". The evidence for this variant shows: a validated functional assay reports phosphatase activity per Mighell et al. 2018 of -3.5729, exceeding the damaging threshold. Therefore, this criterion is applied at Moderate strength because the PTEN-specific functional score meets the PS3_moderate threshold.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Probands with specificity score 4-15.5 OR increased prevalence in cases vs controls...". The evidence for this variant shows: no case-control or proband-specific data are available. 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 (residues 90-94, 123-130, 166-168)...". The evidence for this variant shows: p.Glu43* lies outside the defined catalytic motifs of PTEN. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent in population Databases present at <0.00001 allele frequency in gnomAD...". The evidence for this variant shows: it is absent from gnomAD and other large population datasets. Therefore, this criterion is applied at Supporting strength because the allele frequency is below the disease-specific threshold.
PM3 (Not Applied)
According to standard ACMG, the rule for PM3 applies to recessive disorders requiring trans observations. The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans observations are relevant. 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...". The evidence for this variant shows: p.Glu43* is a nonsense variant, 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 nonsense variant, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Strong/Very Strong Strength: Assumed de novo observations without confirmation...". The evidence for this variant shows: no de novo or familial 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 reported. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG, the rule for PP2 is: "Supporting Strength: Missense variant in a gene with low benign missense variation where missense is common mechanism...". The evidence for this variant shows: it is a nonsense change. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect... Splicing variants: Concordance of SpliceAI and VarSeak...". The evidence for this variant shows: SpliceAI predicts donor loss with a score of 0.53 supporting splicing impact, and other in silico tools show potential damage. Therefore, this criterion is applied at Supporting strength because computational evidence indicates a deleterious effect.
PP4 (Not Applied)
According to standard ACMG, the rule for PP4 is: "Phenotype specificity for a single genetic etiology...". The evidence for this variant shows: no patient phenotype data were provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG, the rule for PP5 is: "Supporting Strength: Reputable source recently reports variant as pathogenic, but evidence is not available to laboratory for independent evaluation". The evidence for this variant shows: ClinVar lists this variant as Pathogenic by three clinical laboratories without accessible primary data. Therefore, this criterion is applied at Supporting strength because a reputable database reports pathogenicity without underlying data.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: gnomAD allele frequency >0.00056...". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: gnomAD allele frequency 0.000043–0.00056...". 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: Observed homozygous in healthy individual...". The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Well-established functional studies show no damaging effect...". The evidence for this variant shows: functional assay indicates damaging effect. 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 exist. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG, the rule for BP1 is: "Supporting Strength: Missense variant in gene where LOF is mechanism...". The evidence for this variant shows: p.Glu43* is a truncating variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Observed in trans with pathogenic PTEN variant...". The evidence for this variant shows: no cis/trans data available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG, the rule for BP3 is: "Supporting Strength: In-frame indels in repetitive regions...". The evidence for this variant shows: p.Glu43* is a nonsense variant, not an in-frame indel. 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...". The evidence for this variant shows: computational tools suggest deleterious effect. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Variant found in case with alternate molecular basis...". The evidence for this variant shows: no alternate genetic etiology reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG, the rule for BP6 is: "Supporting Strength: Reputable source reports variant as benign...". The evidence for this variant shows: no benign assertions in reputable sources. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Synonymous or intronic variant at or beyond +7/-21 with no splicing impact...". The evidence for this variant shows: p.Glu43* is a nonsense coding variant. Therefore, this criterion is not applied.