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
Open"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN H123Pfs*11 variant is a truncating mutation that results in the loss of PTEN phosphatase function. This loss of function impairs the negative regulation of the PI3K/AKT pathway, contributing to oncogenic activity. Functional studies have demonstrated that such truncating mutations in PTEN lead to increased genome fragility and an inability to associate with chromosomal centromeres, supporting a damaging effect.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -75 bp |
| Donor Loss (DL) | 0.0 | 129 bp |
| Acceptor Gain (AG) | 0.01 | -5 bp |
| Donor Gain (DG) | 0.0 | 125 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines: "Very Strong: Null variant (nonsense, frameshift, start codon, etc.) in a gene where LOF is a known mechanism of disease." The evidence shows that c.368del (H123Pfs*11) is a frameshift predicted to result in NMD in PTEN, a gene with haploinsufficiency. Therefore, PVS1 is applied at Very Strong strength because it is a truncating null variant in a gene where LOF causes disease.
PS1 (Not Applied)
According to VCEP guidelines: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change…" The evidence shows this is a frameshift variant, not a missense change recreating a known pathogenic amino acid substitution. Therefore, PS1 is not applied because the rule is not met.
PS2 (Not Applied)
According to VCEP guidelines: "Very Strong: Two proven or four assumed de novo observations…" There are no data on de novo occurrence for this variant. Therefore, PS2 is not applied due to lack of de novo evidence.
PS3 (Strong)
According to VCEP guidelines: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence shows functional studies demonstrate loss of PTEN phosphatase activity, genome instability, and failure to regulate PI3K/AKT pathway. Therefore, PS3 is applied at Strong strength because functional assays support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines: "Strong: Prevalence of variant in affected individuals is significantly increased compared with controls or probands with specificity score 4–15.5…" There are no case‐control data or proband specificity scores. Therefore, PS4 is not applied due to absence of evidence.
PM1 (Not Applied)
According to VCEP guidelines: "Moderate: Located in a mutational hotspot or critical functional domain (residues 90–94, 123–130)." The variant is a frameshift and not a missense change within these residues. Therefore, PM1 is not applied because the rule applies only to missense variants.
PM2 (Supporting)
According to VCEP guidelines: "Supporting: Absent in population databases present at <0.00001 allele frequency." The variant is absent from gnomAD, ESP, and 1000 Genomes. Therefore, PM2 is applied at Supporting strength because it is absent in controls.
PM3 (Not Applied)
According to standard ACMG guidelines: "Moderate: For recessive disorders, detected in trans with a pathogenic variant…" PTEN disease is autosomal dominant and no trans observations exist. Therefore, PM3 is not applied due to non‐applicability in a dominant context.
PM4 (Not Applied)
According to standard ACMG guidelines: "Moderate: Protein length changes due to in-frame indels…" This variant is a frameshift truncation appropriately evaluated under PVS1. Therefore, PM4 is not applied because PVS1 covers null variants.
PM5 (Not Applied)
According to VCEP guidelines: "Moderate: Missense change at a residue where a different missense change determined to be pathogenic has been seen." The variant is a frameshift, not a missense change. Therefore, PM5 is not applied because it does not meet the missense requirement.
PM6 (Not Applied)
According to VCEP guidelines: "Strong/Very Strong/Moderate: Assumed de novo occurrences…" No presumed de novo data are available. Therefore, PM6 is not applied due to lack of de novo evidence.
PP1 (Not Applied)
According to VCEP guidelines: "Supporting: Co-segregation with disease in multiple affected family members (3–4 meioses)…" There are no segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines: "Supporting: Missense variant in a gene with low rate of benign missense variation…" The variant is not a missense change. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines: "Supporting: Multiple lines of computational evidence support a deleterious effect…" The variant is a frameshift null change, and computational splicing predictions show minimal impact on splicing but are irrelevant to its LOF effect. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines: "Supporting: Patient’s phenotype is highly specific for a disease with single genetic etiology…" No phenotype data were provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: "Supporting: Reputable source reports variant as pathogenic…" ClinVar classifies this variant as VUS, not (likely) pathogenic. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines: "Stand Alone: Allele frequency >0.00056…" The variant is not frequent. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines: "Strong: Allele frequency 0.000043–0.00056…" The variant frequency is zero. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines: "Strong: Observed homozygous in healthy…" No homozygous observations exist. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines: "Strong: Functional studies show no damaging effect…" Functional studies show damaging effect. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines: "Strong: Lack of segregation in affected members…" No segregation data. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines: "Supporting: Missense variant in a gene where truncating variants are known mechanism…" The variant is truncating and not missense. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines: "Supporting: Observed in trans with pathogenic variant…" No such observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines: "Supporting: In-frame indels in repetitive region…" The variant is a frameshift truncation. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines: "Supporting: Multiple lines of computational evidence suggest no impact…" Although splicing algorithms predict minimal impact, the variant causes LOF by frameshift. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to VCEP guidelines: "Supporting: Variant found with alternate molecular basis…" No alternate molecular basis reported. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines: "Supporting: Reputable source labels as benign…" ClinVar lists as VUS, not benign. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines: "Supporting: Synonymous or intronic variant…" The variant is not synonymous or intronic. Therefore, BP7 is not applied.