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 F241S variant has been functionally characterized and demonstrates a damaging effect. It is located in the phosphatase domain of the PTEN protein and results in loss of phosphatase activity, decreased protein stability, and reduced nuclear localization. Functional assays in yeast, glioblastoma cell lines, and Drosophila models show that this variant leads to loss of PTEN function, acts as a dominant negative regulator of the PI3-AKT signaling pathway, and delays developmental growth.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -87 bp |
| Donor Loss (DL) | 0.0 | -6 bp |
| Acceptor Gain (AG) | 0.01 | -33 bp |
| Donor Gain (DG) | 0.0 | -108 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Use PTEN PVS1 decision tree." The evidence for this variant shows: c.722T>C (p.F241S) is a missense change, not a null variant. Therefore, this criterion is not applied because PVS1 applies only to predicted loss‐of‐function variants as per the PTEN PVS1 decision tree.
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..." The evidence for this variant shows: no other PTEN variant at p.Phe241 has been reported as pathogenic. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "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 data are available. Therefore, PS2 is not applied.
PS3 (Moderate)
According to PTEN Pre-processing, the finding for PS3 is: "Applied PS3_Moderate evidence based on high-confidence functional score (-2.3994) < threshold (-1.11)." The evidence for this variant shows: multiple well-established functional assays demonstrate loss of PTEN phosphatase activity, decreased stability, and dominant-negative effect. Therefore, PS3 is applied at Moderate strength because the variant meets the PTEN-specific phosphatase activity threshold.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Probands with specificity score ≥4 or significantly increased prevalence in affected versus controls." The evidence for this variant shows: no case‐level or cohort data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical functional domain: residues 90-94, 123-130, 166-168." The evidence for this variant shows: p.Phe241 lies outside these defined catalytic motifs. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Absent in population databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows: not observed in gnomAD or other large controls. Therefore, PM2 is applied at Supporting strength.
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 shows: no evidence of recessive biallelic occurrence. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a missense change without protein length alteration. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Missense change at a residue where a different missense change is pathogenic." The evidence for this variant shows: no other pathogenic missense reported at p.Phe241. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo without confirmation." The evidence for this variant shows: no de novo assumption data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in family members." The evidence for this variant shows: no segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense in a gene with low rate of benign missense and where missense is common disease mechanism." The evidence for this variant shows: insufficient data on benign missense rate in PTEN. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Multiple lines of computational evidence support deleterious effect; REVEL >0.7." The evidence for this variant shows: mixed in silico predictions and no consensus REVEL >0.7. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype highly specific for gene." The evidence for this variant shows: no phenotype data. Therefore, PP4 is not applied.
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: not found in ClinVar or other databases. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "gnomAD allele frequency >0.00056." The evidence for this variant shows: allele frequency = 0%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "gnomAD allele frequency from 0.0043% to 0.056%." The evidence for this variant shows: allele frequency = 0%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed homozygous in healthy individual." The evidence for this variant shows: no homozygous observations. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense in gene where only truncating variants cause disease." The evidence for this variant shows: PTEN missense variants are known to be disease-causing. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic PTEN variant." The evidence for this variant shows: no trans observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in repetitive region without functional impact." The evidence for this variant shows: not an indel. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact; REVEL <0.5." The evidence for this variant shows: in silico predictions are mixed with some pathogenic scores. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Variant found with alternate molecular basis." The evidence for this variant shows: no alternate molecular diagnosis. Therefore, BP5 is not applied.
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 such reports. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous variant with no splicing impact." The evidence for this variant shows: it is missense. Therefore, BP7 is not applied.