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
OpenThe c.43A>T (p.R15*) alteration, located in exon 1 (coding exon 1) of the PTEN gene, consists of an A to T substitution at nucleotide position 43. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 15. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell, 2018). In addition, this variant demonstrated possibly low intracellular protein abundance in a massively parallel functional assay (Matreyek, 2018). Based on the available evidence, this alteration is classified as pathogenic.
This sequence change creates a premature translational stop signal (p.Arg15*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1422662). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN R15* variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that expression of this truncation in mouse embryonic fibroblasts leads to oncogenic effects and increased genomic fragility due to the inability of the truncated 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) | 0.09 | -58 bp |
| Donor Loss (DL) | 0.22 | 36 bp |
| Acceptor Gain (AG) | 0.0 | -262 bp |
| Donor Gain (DG) | 0.62 | -2 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.43A>T is a nonsense variant predicted to result in loss of PTEN function. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where loss of function is a known mechanism of disease.
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: There is no previously established pathogenic variant encoding R15*. 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 in a patient with the disease and no family history.". 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: "Applied PS3_Moderate (Score -2.7576 < -1.11)". The evidence for this variant shows: Well-established functional studies demonstrate loss of PTEN phosphatase activity for R15*. Therefore, this criterion is applied at Moderate strength because the high-confidence functional score meets the VCEP threshold.
PS4 (Not Applied)
According to VCEP guidelines the rule for PS4 is: "Strong Strength: Probands with specificity score 4-15.5 OR significant increased prevalence in cases vs controls.". The evidence for this variant shows: No case-control or proband specificity 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: Position R15 is outside defined 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 allele frequency in gnomAD or another large sequenced population.". The evidence for this variant shows: The variant is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it meets the VCEP frequency threshold.
PM3 (Not Applied)
According to VCEP guidelines the rule for PM3 is: "Moderate Strength: Evidence for recessive disorders (observed in trans with a pathogenic variant).". The evidence for this variant shows: PTEN disorders are autosomal dominant and no trans observations are reported. 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 indels or stop-loss variants.". The evidence for this variant shows: It is a nonsense variant, not an in-frame indel or stop-loss. 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: This is a nonsense, not a missense variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines the rule for PM6 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations...". The evidence for this variant shows: No presumed de novo data are available. 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 (3-4 meioses).". The evidence for this variant shows: No segregation data are provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG the rule for PP2 is: "Supporting Missense variant in a gene with low rate of benign missense variation and where missense variants are common mechanism.". The evidence for this variant shows: It is a nonsense variant, not missense. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product.". The evidence for this variant shows: SpliceAI predicts a moderate impact on splicing and in silico tools indicate likely deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence supports a damaging effect.
PP4 (Not Applied)
According to standard ACMG the rule for PP4 is: "Supporting Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.". The evidence for this variant shows: No detailed phenotypic information is provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG the rule for PP5 is: "Supporting Reputable source recently reports variant as pathogenic, but evidence not available for independent evaluation.". The evidence for this variant shows: ClinVar reports this variant as Pathogenic in three clinical laboratories. Therefore, this criterion is applied at Supporting strength because of the reputable pathogenic assertions.
BA1 (Not Applied)
According to VCEP guidelines the rule for BA1 is: "Stand Alone Strength: gnomAD Filtering allele frequency >0.00056.". The evidence for this variant shows: Frequency is 0%, not above threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines the rule for BS1 is: "Strong Strength: gnomAD Filtering allele frequency 0.000043–0.00056.". The evidence for this variant shows: Frequency is 0%, below threshold. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines the rule for BS2 is: "Strong Strength: Observed homozygous in healthy individuals.". The evidence for this variant shows: No homozygous observations in unaffected individuals. 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 studies demonstrate 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 indicate lack of segregation. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG the rule for BP1 is: "Supporting Missense variant in gene where only loss-of-function causes disease.". The evidence for this variant shows: It is a truncating variant, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines the rule for BP2 is: "Supporting Observed in trans with a pathogenic PTEN variant OR multiple cis observations.". The evidence for this variant shows: No such observations reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines the rule for BP3 is: "Supporting In-frame indel in repetitive region.". The evidence for this variant shows: It 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 Multiple lines of computational evidence suggest no impact.". The evidence for this variant shows: Computational tools predict deleterious impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines the rule for BP5 is: "Supporting Variant found in a case with an alternate molecular basis for disease.". The evidence for this variant shows: No alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG the rule for BP6 is: "Supporting Reputable source reports benign but evidence unavailable.". The evidence for this variant shows: No reputable benign assertions exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines the rule for BP7 is: "Supporting Synonymous or intronic variant with no splicing impact.". The evidence for this variant shows: It is a nonsense variant. Therefore, this criterion is not applied.