PTEN c.724_728dup, p.Phe243LeufsTer15
NM_000314.8:c.724_728dup
Pathogenic
The c.724_728dup (F243Lfs*15) variant in PTEN leads to a premature truncation and loss of phosphatase function. It meets PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting), classifying it as Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.724_728dup
Protein Change
F243Lfs*15
Location
Exon 7
(Exon 7 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 243 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.724_728dup
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 243 in gene PTEN
Functional Summary
The PTEN F243Lfs*15 variant is a truncating mutation that results in the loss of PTEN phosphatase function. This loss of function impairs the ability of PTEN to negatively regulate PI3K/AKT pathway activity, leading to oncogenic effects. Functional studies have shown that PTEN truncation mutations can increase genome fragility and disrupt chromosomal centromere association, contributing to their oncogenic potential.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Strength: Use PTEN PVS1 decision tree.' The evidence for this variant shows: NM_000314.8:c.724_728dup causes a frameshift (F243Lfs*15) leading to a premature stop codon not in the last exon. Therefore, this criterion is applied at Very Strong strength because a null variant in PTEN, where loss of function is a known disease mechanism, meets the PTEN-specific decision tree for PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong: 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 at codon F243 or the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rules for PS2 are: 'Very Strong: Two proven OR four assumed OR one proven + two assumed de novo observations' and 'Strong: De novo (both maternity and paternity confirmed) observation.' The evidence for this variant shows: no parental testing or de novo evidence. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 (Strong) is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' According to PTEN pre-processing, the finding for PS3 is: 'The PTEN F243Lfs*15 variant is a truncating mutation that results in the loss of PTEN phosphatase function ... Functional studies have shown that PTEN truncation mutations can increase genome fragility and disrupt chromosomal centromere association.' The evidence for this variant shows: confirmed loss of phosphatase activity and oncogenic functional impact. Therefore, this criterion is applied at Strong strength because well-established functional studies demonstrate a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong: Probands with specificity score 4-15.5 or increased prevalence in cases vs controls.' The evidence for this variant shows: no case-control data or proband specificity scoring available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate: Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168).' The evidence for this variant shows: position F243 lies outside known PTEN hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting: Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).' The evidence for this variant shows: MAF = 0% in gnomAD and other large databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no evidence of trans observations or recessive inheritance. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate: 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 frameshift leading to premature truncation, covered by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence for this variant shows: this is a frameshift, not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Very Strong: Two proven OR four assumed OR one proven + two assumed de novo observations; Strong: two presumed de novo without confirmation.' The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting: Co-segregation with disease in multiple affected family members (3–4 meioses).' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting: Missense variant in a gene that has a low rate of benign missense variation where missense variants are a common mechanism.' The evidence for this variant shows: this is a truncating variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting: Multiple lines of computational evidence support a deleterious effect (REVEL > 0.7 for missense; concordant splicing predictors for splicing).' The evidence for this variant shows: in silico splice prediction (SpliceAI score 0.02) does not indicate impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting: 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.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting: Reputable source reports variant as pathogenic without accessible evidence.' The evidence for this variant shows: no such non-expert assertions. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: gnomAD Filtering allele frequency >0.00056.' The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: gnomAD Filtering allele frequency from 0.000043 up to 0.00056.' The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed homozygous in a healthy individual; Supporting if two observations without clinical data.' The evidence for this variant shows: no homozygous observations in controls. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong: Functional studies show no damaging effect; Supporting: phosphatase activity >0.' The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong: Lack of segregation in two or more families; Supporting: lack of segregation in one family.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting: Missense variant in a gene where only truncating variants cause disease.' The evidence for this variant shows: it is itself a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Supporting: Observed in trans with a pathogenic PTEN variant or ≥3 cis observations.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting: In-frame indel in a repetitive region without known function.' The evidence for this variant shows: it is a frameshift outside a repeat region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting: Multiple lines of computational evidence suggest no impact.' The evidence for this variant shows: computational data are irrelevant for a truncating variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting: Variant found in a case with an alternate molecular basis.' The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP6 is: 'Supporting: Reputable source reports variant as benign without accessible evidence.' The evidence for this variant shows: no such assertions. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting: Synonymous or intronic variant at +7/-21 with no splicing impact.' The evidence for this variant shows: it is a frameshift, not synonymous or intronic. Therefore, this criterion is not applied.