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 L140Nfs*3 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 PTEN's association with chromosomal centromeres.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.06 | -180 bp |
| Donor Loss (DL) | 0.0 | 55 bp |
| Acceptor Gain (AG) | 0.28 | 26 bp |
| Donor Gain (DG) | 0.0 | 462 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Use PTEN PVS1 decision tree". The evidence for this variant shows a frameshift (L140Nfs*3) predicted to undergo loss-of-function in a gene where LOF is a known mechanism of disease, and it does not fall in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant satisfies the PTEN-specific LOF decision tree for PVS1.
PS3 (Strong)
According to PTEN Pre-processing findings, the rule for PS3 is: "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 that functional assays demonstrate loss of PTEN phosphatase activity and oncogenic effects of truncating mutations at L140Nfs*3. Therefore, this criterion is applied at Strong strength because PTEN-specific functional data confirm a damaging impact.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "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 a 0% minor allele frequency in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "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 previously established pathogenic variant at the same amino acid or nucleotide position. Therefore, this criterion is not applied because there is no existing pathogenic variant match.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong 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 includes no confirmed de novo occurrences. Therefore, this criterion is not applied because de novo status is not established.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls, or probands with specificity score 4-15.5". The evidence for this variant includes no case-control or proband specificity data. Therefore, this criterion is not applied because there is no observational data on increased prevalence in affected individuals.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "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 a frameshift at residue 140, outside defined critical motifs. Therefore, this criterion is not applied because the variant does not lie within a designated hotspot or functional domain.
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 includes no information on trans observations with another PTEN pathogenic allele. Therefore, this criterion is not applied because trans configuration data are not available.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region". The evidence for this variant shows a frameshift leading to truncation, not an in-frame indel. Therefore, this criterion is not applied because PM4 applies only to in-frame events.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Missense change at a residue where a different missense pathogenic variant was seen before". The evidence for this variant shows a frameshift, not a missense change. Therefore, this criterion is not applied because PM5 is limited to missense variants.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity and maternity". The evidence for this variant includes no de novo data. Therefore, this criterion is not applied because assumed de novo status is not documented.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant includes no segregation data. Therefore, this criterion is not applied because family segregation information is lacking.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense variants are common mechanism of disease". The evidence for this variant shows a frameshift, not a missense variant. Therefore, this criterion is not applied because PP2 is specific to missense changes.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect (e.g., SpliceAI, REVEL)". The evidence for this variant includes a SpliceAI score of 0.28 and no concordant high-confidence deleterious predictions. Therefore, this criterion is not applied because computational evidence is insufficient to predict deleterious impact.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". The evidence for this variant includes no detailed phenotype data. Therefore, this criterion is not applied because specific phenotypic correlation is not provided.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic". The evidence for this variant shows no ClinVar or other authoritative classifications. Therefore, this criterion is not applied because no external pathogenic assertions are available.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "gnomAD Filtering allele frequency >0.00056 (0.056%)". The evidence for this variant shows a 0% allele frequency. Therefore, this criterion is not applied because the allele frequency is well below the BA1 threshold.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "gnomAD Filtering allele frequency from 0.000043 up to 0.00056". The evidence for this variant shows a 0% allele frequency. Therefore, this criterion is not applied because the allele frequency does not meet BS1 thresholds.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed in homozygous state in a healthy individual". The evidence for this variant includes no homozygous observations. Therefore, this criterion is not applied because no healthy homozygotes are reported.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Functional studies show no damaging effect". The evidence for this variant shows functional impairment. Therefore, this criterion is not applied because functional data indicate damage, not lack thereof.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected members". The evidence for this variant includes no segregation studies. Therefore, this criterion is not applied because segregation data are unavailable.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where LOF is the only known mechanism". The evidence for this variant shows a frameshift LOF event, not missense. Therefore, this criterion is not applied because BP1 applies only to missense variants.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic PTEN variant or multiple cis observations". The evidence for this variant includes no allelic phase data. Therefore, this criterion is not applied because trans or cis observations with other PTEN variants are not documented.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive region". The evidence for this variant shows a frameshift deletion, not an in-frame event in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant includes conflicting in silico predictions and a subthreshold SpliceAI score. Therefore, this criterion is not applied because benign computational evidence is insufficient.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant includes no alternate molecular diagnosis. Therefore, this criterion is not applied because no competing genetic etiology is reported.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign". The evidence for this variant shows no benign assertions. Therefore, this criterion is not applied because no external benign reports exist.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant with no splicing impact". The evidence for this variant shows a coding frameshift. Therefore, this criterion is not applied because BP7 pertains to synonymous or intronic changes.