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 p.R15G variant (also known as c.43A>G), located in coding exon 1 of the PTEN gene, results from an A to G substitution at nucleotide position 43. The arginine at codon 15 is replaced by glycine, an amino acid with dissimilar properties. Based on internal structural analysis, R15G is disrupts a residue within the functionally critical NLS motif (Gil A et al. PLoS One, 2015 Apr;10:e0119287; Das S et al. Proc Natl Acad Sci U S A, 2003 Jun;100:7491-6; Dempsey DR et al. Nat Struct Mol Biol, 2021 Oct;28:858-868). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 (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) | 0.05 | -58 bp |
| Donor Loss (DL) | 0.04 | 36 bp |
| Acceptor Gain (AG) | 0.01 | -473 bp |
| Donor Gain (DG) | 0.0 | 152 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 for null variants (nonsense, frameshift, canonical ±1/2 splice sites, start codon, single or multi-exon deletions) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: NM_000314.8:c.43A>G (p.Arg15Gly) is a missense change, not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet PVS1 requirements.
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: p.Arg15Gly is not the same amino acid change as any known pathogenic PTEN variant. Therefore, this criterion is not applied at Not Applied strength because no identical amino acid change has been reported as pathogenic.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied at Not Applied strength because de novo occurrence has not been demonstrated.
PS3 (Moderate)
According to PTEN Pre-processing, the rule/finding for PS3_moderate is: "Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350) indicates a damaging effect on the gene product." The evidence for this variant shows: a high-confidence functional score of -1.3235, which is below the -1.11 threshold. Therefore, this criterion is applied at Moderate strength because the variant meets the PTEN-specific PS3_moderate threshold.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Significantly increased prevalence in affected individuals compared with controls or proband specificity score ≥4." The evidence for this variant shows: no case-control or proband data are available. Therefore, this criterion is not applied at Not Applied strength because prevalence in affected individuals has not been established.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hotspot and/or critical and well-established functional domain (residues 90–94, 123–130, 166–168)." The evidence for this variant shows: p.Arg15Gly lies outside these defined catalytic motifs. Therefore, this criterion is not applied at Not Applied strength because the residue is not within a PTEN mutational hotspot or critical domain.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2_supporting is: "Absent in population databases present at <0.00001 allele frequency in gnomAD or another large sequenced population." The evidence for this variant shows: 0% allele frequency in gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant in recessive disorders." The evidence for this variant shows: PTEN-related disease is autosomal dominant and there is no evidence of trans configuration. Therefore, this criterion is not applied at Not Applied strength because it is not relevant to the inheritance pattern.
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: p.Arg15Gly is a missense substitution, not an in-frame indel or protein-extending variant. Therefore, this criterion is not applied at Not Applied strength.
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5_moderate 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: Arg15 has a known pathogenic missense (p.Arg15His). Therefore, this criterion is applied at Moderate strength because p.Arg15Gly occurs at a residue with a previously established pathogenic missense variant.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity and maternity." The evidence for this variant shows: no presumed de novo occurrences reported. Therefore, this criterion is not applied at Not Applied strength because assumed de novo status has not been 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 shows: no segregation data are available. Therefore, this criterion is not applied at Not Applied strength because familial co-segregation has not been demonstrated.
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 where missense is a common disease mechanism." The evidence for this variant shows: PTEN has both benign and pathogenic missense variants; gene-level constraint is not sufficiently low to apply PP2. Therefore, this criterion is not applied at Not Applied strength.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3_supporting is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (REVEL score >0.7)." The evidence for this variant shows: REVEL score = 0.78, SpliceAI max = 0.05 (no splicing impact), and other in silico tools predict deleterious. Therefore, this criterion is applied at Supporting strength because computational evidence supports a damaging effect.
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 shows: no detailed phenotype specificity data provided. Therefore, this criterion is not applied at Not Applied strength because phenotype data are insufficient.
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: ClinVar lists it as Uncertain significance. Therefore, this criterion is not applied at Not Applied strength because no reputable source has classified it as pathogenic.
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 = 0%. Therefore, this criterion is not applied at Not Applied strength because the variant is not at high population frequency.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "gnomAD allele frequency from 0.000043 to 0.00056." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied at Not Applied strength because the variant frequency does not meet BS1 thresholds.
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 in healthy individuals. Therefore, this criterion is not applied at Not Applied strength.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect (phosphatase activity >0)." The evidence for this variant shows: functional assay indicates damaging effect. Therefore, this criterion is not applied at Not Applied strength.
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 studies. Therefore, this criterion is not applied at Not Applied strength.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows: PTEN pathogenic missense variants are known. Therefore, this criterion is not applied at Not Applied strength.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic PTEN variant or in cis with multiple. " The evidence for this variant shows: no such observations. Therefore, this criterion is not applied at Not Applied strength.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame indels in a repetitive region without a known function." The evidence for this variant shows: missense change, not in‐frame indel. Therefore, this criterion is not applied at Not Applied strength.
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: REVEL = 0.78, supporting a deleterious effect. Therefore, this criterion is not applied at Not Applied strength.
BP5 (Not Applied)
According to standard ACMG 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 basis reported. Therefore, this criterion is not applied at Not Applied strength.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports the variant as benign." The evidence for this variant shows: ClinVar reports VUS. Therefore, this criterion is not applied at Not Applied strength.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic ≥±7 without splicing impact." The evidence for this variant shows: it is missense. Therefore, this criterion is not applied at Not Applied strength.