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
OpenPatient, a 4 year-old girl, showed mild developmental delay, hypotonia, and dysmorphic facial features. Her last head circumference was 56.5 cm (+4.0SD). This mutation was confirmed de novo. The expression level of phosphorylated S6 ribosomal protein in her lymphoblastoid cell line was elevated.
"This variant has been reported in ClinVar as Likely pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen expert panel."
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 | -249 bp |
| Donor Loss (DL) | 0.0 | -126 bp |
| Acceptor Gain (AG) | 0.04 | -51 bp |
| Donor Gain (DG) | 0.0 | -203 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines the rule/finding for PVS1 is: Use PTEN PVS1 decision tree for loss-of-function variants. The evidence for this variant shows: c.740T>C is a missense variant and does not introduce a premature stop or alter a canonical splice site. Therefore, this criterion is not applied because the variant is not expected to result in loss of function.
PS1 (Not Applied)
According to VCEP guidelines the rule/finding 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. The evidence for this variant shows: no previously established pathogenic variant resulting in Leu247Ser. Therefore, this criterion is not applied because there is no matching amino acid change reported as pathogenic.
PS2 (Not Applied)
According to VCEP guidelines the rule/finding for PS2 is: Very Strong de novo or Strong de novo with confirmation of maternity and paternity. The evidence for this variant shows: no de novo occurrence data available. Therefore, this criterion is not applied because de novo status has not been established.
PS3 (Moderate)
According to PTEN Pre-processing guidelines the finding for PS3 is: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. The evidence for this variant shows: functional score of -1.6698 which is below the threshold of -1.11. Therefore, this criterion is applied at Moderate strength because the variant meets the PTEN-specific functional assay threshold.
PS4 (Not Applied)
According to VCEP guidelines the rule/finding for PS4 is: Probands with specificity score ≥16 for Very Strong or 4–15.5 for Strong. The evidence for this variant shows: no proband specificity score data available. Therefore, this criterion is not applied because case prevalence data are lacking.
PM1 (Not Applied)
According to VCEP guidelines the rule/finding for PM1 is: Located in a mutational hotspot and/or critical functional domain defined to include residues in catalytic motifs: 90-94, 123-130, 166-168. The evidence for this variant shows: Leu247 is outside of these PTEN catalytic motifs. Therefore, this criterion is not applied because the residue is not in a defined hotspot or critical domain.
PM2 (Supporting)
According to VCEP guidelines the rule/finding for PM2 is: Absent in population databases present at <0.00001 allele frequency in gnomAD. The evidence for this variant shows: variant is not found in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because of absence from controls.
PM3 (Not Applied)
According to standard ACMG guidelines the rule/finding for PM3 is: For recessive disorders, detected in trans with a pathogenic variant supports moderate evidence. The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans observation with a pathogenic PTEN variant. Therefore, this criterion is not applied because PM3 is not relevant for dominant inheritance.
PM4 (Not Applied)
According to VCEP guidelines the rule/finding for PM4 is: Protein length changes due to in-frame insertions/deletions in non-repeat regions. The evidence for this variant shows: this is a missense substitution with no change in protein length. Therefore, this criterion is not applied because there is no protein length alteration.
PM5 (Not Applied)
According to VCEP guidelines the rule/finding for PM5 is: Missense change at a residue where a different missense change determined to be pathogenic has been seen before. The evidence for this variant shows: no other missense variants at Leu247 have been reported as pathogenic. Therefore, this criterion is not applied because no prior pathogenic missense at this residue is known.
PM6 (Not Applied)
According to VCEP guidelines the rule/finding for PM6 is: Assumed de novo without parental confirmation. The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied because there is no assumed de novo evidence.
PP1 (Not Applied)
According to VCEP guidelines the rule/finding for PP1 is: Co-segregation with disease in multiple affected family members. The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied because familial segregation has not been assessed.
PP2 (Supporting)
According to standard ACMG guidelines the rule/finding 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: PTEN is intolerant of benign missense and missense variants are known to cause PTEN-related disorders. Therefore, this criterion is applied at Supporting strength because of the gene's intolerance and disease mechanism.
PP3 (Supporting)
According to VCEP guidelines the rule/finding for PP3 is: Multiple lines of computational evidence support a deleterious effect, with REVEL score > 0.7. The evidence for this variant shows: REVEL score of 0.92, PolyPhen, MetaSVM, MetaLR, PrimateAI and Deogen2 predict damaging. Therefore, this criterion is applied at Supporting strength because of consistent damaging in silico predictions.
PP4 (Not Applied)
According to standard ACMG guidelines the rule/finding 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 phenotype data provided. Therefore, this criterion is not applied because phenotype specificity cannot be evaluated.
PP5 (Supporting)
According to standard ACMG guidelines the rule/finding for PP5 is: Reputable source reports variant as pathogenic but the evidence is unavailable for independent evaluation. The evidence for this variant shows: ClinVar entry by ClinGen PTEN VCEP lists Likely Pathogenic. Therefore, this criterion is applied at Supporting strength because of the reputable external assertion.
BA1 (Not Applied)
According to VCEP guidelines the rule/finding for BA1 is: gnomAD filtering allele frequency > 0.00056. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied because allele frequency is not above the threshold.
BS1 (Not Applied)
According to VCEP guidelines the rule/finding for BS1 is: gnomAD allele frequency from 0.000043 up to 0.00056. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied because the frequency is below the benign range.
BS2 (Not Applied)
According to VCEP guidelines the rule/finding for BS2 is: Observed homozygous in a healthy individual. The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied because no unaffected homozygotes are documented.
BS3 (Not Applied)
According to VCEP guidelines the rule/finding for BS3 is: Well-established functional studies show no damaging effect, with phosphatase activity > 0. The evidence for this variant shows: measured activity is below threshold indicating damaging effect. Therefore, this criterion is not applied because functional data support damage.
BS4 (Not Applied)
According to VCEP guidelines the rule/finding for BS4 is: Lack of segregation in affected members of families. The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied because segregation data are absent.
BP1 (Not Applied)
According to standard ACMG guidelines the rule/finding for BP1 is: Missense variant in a gene where truncating variants are the only known mechanism of disease. The evidence for this variant shows: missense is a known mechanism for PTEN-related disorders. Therefore, this criterion is not applied because missense variants are established pathogenic mechanisms.
BP2 (Not Applied)
According to VCEP guidelines the rule/finding for BP2 is: Observed in trans with a pathogenic PTEN variant or multiple cis observations. The evidence for this variant shows: no trans or cis observations. Therefore, this criterion is not applied because no such observations exist.
BP3 (Not Applied)
According to standard ACMG guidelines the rule/finding for BP3 is: In-frame deletions/insertions in repetitive regions without known function. The evidence for this variant shows: this is a missense substitution. Therefore, this criterion is not applied because it is not an in-frame indel.
BP4 (Not Applied)
According to VCEP guidelines the rule/finding for BP4 is: Multiple lines of computational evidence suggest no impact, with REVEL < 0.5. The evidence for this variant shows: REVEL is 0.92 indicating damaging effect. Therefore, this criterion is not applied because computational predictions support deleterious effect.
BP5 (Not Applied)
According to VCEP guidelines the rule/finding 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 because no such case is documented.
BP6 (Not Applied)
According to standard ACMG guidelines the rule/finding for BP6 is: Reputable source reports variant as benign but evidence is unavailable. The evidence for this variant shows: no reputable source reports benign. Therefore, this criterion is not applied because there is no benign assertion.
BP7 (Not Applied)
According to VCEP guidelines the rule/finding for BP7 is: Synonymous variant predicted to have no splicing impact. The evidence for this variant shows: this is a missense variant. Therefore, this criterion is not applied because BP7 applies only to silent or intronic variants.