Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
| 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 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe c.74T>C (p.L25S) alteration is located in exon 1 (coding exon 1) of the PTEN gene. This alteration results from a T to C substitution at nucleotide position 74, causing the leucine (L) at amino acid position 25 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, c.75G>T (p.L25F), has been detected in multiple individuals with features consistent with PTEN hamartoma tumor syndrome (Tan, 2011; Ciaccio, 2019; Ronzano, 2022). 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, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -142 bp |
| Donor Loss (DL) | 0.06 | 5 bp |
| Acceptor Gain (AG) | 0.06 | -89 bp |
| Donor Gain (DG) | 0.07 | 94 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows: it is a missense change (L25S), not a null variant. Therefore, this criterion is not applied.
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 other variant at codon 25 (L25) has been previously established as pathogenic. Therefore, this criterion 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 available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to PTEN pre-processing, the finding for PS3 is: "Result: High confidence not TRUE ('FALSE'), PS3 rule not applied." The evidence for this variant shows: no well-established functional assay evidence. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls or probands with specificity score ≥4". The evidence for this variant shows: no case-control or proband specificity data provided. Therefore, this criterion is not applied.
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. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168." The evidence for this variant shows: residue 25 is outside these regions. Therefore, this criterion is not applied.
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: it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Observed in trans with a pathogenic or likely pathogenic PTEN variant in a recessive disorder." The evidence for this variant shows: no data on trans configuration with another variant. Therefore, this criterion is not applied.
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 or stop-loss variants." The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "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: no other missense at residue 25 reported as pathogenic. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo occurrence in a patient with the disease and no family history (without confirmation of paternity and maternity)." The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
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 shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP guidelines, the rule for PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: no specific data on benign missense rate in PTEN. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Missense variants: REVEL score > 0.7." The evidence for this variant shows: REVEL score of 0.94, exceeding the 0.7 threshold. Therefore, this criterion is applied at Supporting strength.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Phenotype specific for disease with single genetic etiology." The evidence for this variant shows: no phenotype information provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: one ClinVar submitter classified it as Pathogenic without available evidence. Therefore, this criterion is applied at Supporting strength.
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: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows: not present in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed in the homozygous state in a healthy or PHTS-unaffected 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: "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows: no functional studies demonstrating no impact. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: PTEN has known pathogenic missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis with different pathogenic variants." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertions or deletions in a repetitive region without a known function." The evidence for this variant shows: missense change, not an in-frame indel. 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. Missense variants: REVEL score < 0.5." The evidence for this variant shows: REVEL score of 0.94, indicating pathogenicity. Therefore, this criterion is not applied.
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 shows: no alternate molecular diagnosis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but evidence not available." The evidence for this variant shows: no benign classification by a reputable source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact." The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.