PTEN c.958_959del, p.Leu320AsnfsTer4
NM_000314.8:c.958_959del
Pathogenic
This PTEN frameshift variant (L320Nfs*4) is a null variant leading to loss of function in a gene where LOF is a known mechanism. Evidence includes PVS1 (Very Strong), PS3 (Strong functional data), PM2 (Supporting), PP5 (Supporting), and BP4 (Supporting). The combination of criteria supports a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
BP4
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.958_959del
Protein Change
L320Nfs*4
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 320 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.958_959del
Active Tracks
ConservationRefSeqClinVargnomAD
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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
1 publications
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PTEN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu320Asnfs*4) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675).
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories).
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 320 in gene PTEN
Functional Summary
The PTEN L320Nfs*4 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that such truncating mutations are oncogenic, increasing genome fragility and impairing PTEN's association with chromosomal centromeres. This evidence supports a damaging effect of the variant.
Database Previews
OncoKB
JAX-CKB
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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 for PTEN, the rule for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: c.958_959del causes a frameshift (L320Nfs*4) predicted to truncate the protein and undergo NMD in a gene where loss-of-function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null variant in PTEN with established LOF pathogenicity.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PS1 is: "Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change..." The evidence for this variant shows: no previously established pathogenic variant results in the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PS2 is: "Strong De novo (both maternity and paternity confirmed) observation..." The evidence for this variant shows: no de novo occurrence data available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product" with evidence that L320Nfs*4 abolishes PTEN phosphatase activity and is oncogenic. Therefore, this criterion is applied at Strong strength because functional studies demonstrate a damaging effect on PTEN.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, 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 or proband specificity data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM1 is: "Moderate Located in a mutational hotspot and/or critical functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: L320 lies outside known catalytic motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM2 is: "Supporting Absent in population databases present at <0.001% allele frequency." The evidence for this variant shows: absent from gnomAD and other large databases. Therefore, this criterion is applied at Supporting strength because it is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: not applicable in an autosomal dominant context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM4 is: "Moderate Protein length changes due to in-frame indels or stop-loss." The evidence for this variant shows: it is a frameshift, not an in-frame event. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM5 is: "Moderate Missense change at a residue where a different pathogenic missense has been seen." The evidence for this variant shows: it is not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM6 is: "Strong assumed de novo without confirmation." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PP1 is: "Supporting co-segregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data. 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 with low rate of benign missense variation." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PP3 is: "Supporting multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: in silico predicts minimal splicing 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 disorder with a single genetic etiology." The evidence for this variant shows: no clinical phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar entry reports it as Pathogenic from one clinical laboratory. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BA1 is: "Stand Alone allele frequency >0.056%." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS1 is: "Strong allele frequency between 0.0043% and 0.056%." The evidence for this variant shows: allele frequency is below this range. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS2 is: "Strong observed homozygous in healthy individual." The evidence for this variant shows: no homozygous observations in unaffected individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS3 is: "Strong well-established functional studies show no damaging effect." 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 for PTEN, the rule for BS4 is: "Strong lack of segregation in affected members." 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 in gene with only LOF mechanism." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BP2 is: "Supporting observed in trans with pathogenic variant." The evidence for this variant shows: no compound observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BP3 is: "Supporting in-frame indels in non-repeat regions." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines for PTEN, the rule for BP4 is: "Supporting multiple lines of computational evidence suggest no impact." The evidence for this variant shows: SpliceAI maximum score 0.01 indicating minimal splicing impact. Therefore, this criterion is applied at Supporting strength because computational data suggest no splicing effect.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BP5 is: "Supporting variant found in case with alternate molecular basis." The evidence for this variant shows: no alternate molecular explanation. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Reputable source reports variant as benign without evidence." The evidence for this variant shows: no such benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BP7 is: "Supporting synonymous or intronic variant with no splicing impact." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.