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 p.F278L variant (also known as c.834C>A), located in coding exon 8 of the PTEN gene, results from a C to A substitution at nucleotide position 834. The phenylalanine at codon 278 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN F278L variant has not been functionally characterized. However, the PTEN F278Lfs*12 frameshift variant, which results in a premature truncation of the PTEN protein, is predicted to lead to a loss of protein function based on the effects of other truncation mutations downstream of this position.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 11 bp |
| Donor Loss (DL) | 0.0 | -12 bp |
| Acceptor Gain (AG) | 0.0 | 260 bp |
| Donor Gain (DG) | 0.0 | 437 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines: PVS1 applies to predicted loss‐of‐function variants per the PTEN PVS1 decision tree. F278L is a missense change and not predicted to cause a null effect. Therefore, this criterion is not applied at any strength because the variant type is not applicable.
PS1 (Not Applied)
According to VCEP guidelines: PS1 requires the same amino acid change as a previously established pathogenic variant. No report of F278L as a known pathogenic change exists. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines: PS2 Strong requires de novo occurrence with maternity and paternity confirmed. No de novo data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to PTEN Pre-processing: the finding for PS3_Moderate is: "Score (-0.2648) did not meet threshold (-1.11) for PS3_Moderate". The variant’s phosphatase activity score is -0.2648. Therefore, PS3 is not applied at any strength because the threshold for damaging functional effect was not met.
PS4 (Not Applied)
According to standard ACMG guidelines: PS4 requires a significantly increased prevalence in affected individuals or appropriate proband counts. No case or cohort data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines: PM1 applies to variants located in a critical PTEN functional domain (residues 90–94, 123–130, or 166–168). F278 lies outside these regions. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines: "PM2 Supporting: Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD". The variant is not found in gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines: PM3 applies to recessive conditions with trans observations alongside a pathogenic variant. PTEN‐related disorders are autosomal dominant and no trans data exist. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines: PM4 applies to protein length changes from in‐frame indels or stop‐loss variants. F278L is a missense change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines: PM5 requires a different missense change at the same residue previously determined pathogenic. No such pathogenic F278 variants are reported. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines: PM6 applies to assumed de novo occurrences without full confirmation. No de novo information is available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines: PP1 requires segregation data in multiple affected family members. No family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines: PP2 applies to missense variants in genes with low benign missense variation and a common missense disease mechanism. PTEN has both missense and truncating pathogenic variants; no evidence supports a low benign missense rate. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines: PP3 Supporting requires REVEL >0.7 for missense. REVEL score is unavailable and in silico predictions are mixed. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines: PP4 applies when the phenotype is highly specific for a single genetic etiology. No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: PP5 applies to non‐independent assertions from reputable sources. ClinVar reports this variant as VUS, which is not an authoritative benign or pathogenic assertion. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines: BA1 requires a gnomAD allele frequency >0.00056. The variant is absent. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines: BS1 applies to allele frequency between 0.000043 and 0.00056. The variant is absent. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines: BS2 requires observation of homozygosity in healthy individuals. No such observations exist. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines: BS3 applies to functional studies showing no damaging effect. No well‐established splicing or functional assay demonstrates lack of impact. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines: BS4 requires lack of segregation in affected family members. No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines: BP1 applies to missense variants in a gene where only loss‐of‐function causes disease. PTEN has known pathogenic missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines: BP2 applies when observed in trans/cis with pathogenic PTEN variants. No such observations exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines: BP3 applies to in‐frame indels in repetitive regions. F278L is a missense change. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines: BP4 for missense requires REVEL <0.5. REVEL score is unavailable and other predictors are mixed. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines: BP5 applies when a variant is found with an alternate molecular basis for disease. No alternate molecular cause data exist. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to VCEP guidelines: BP6 applies to low‐quality assertions from reputable sources. ClinVar’s VUS classification lacks sufficient evidence quality. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines: BP7 applies to synonymous or intronic variants with no splicing impact. F278L is missense. Therefore, this criterion is not applied.