PTEN c.947del, p.Leu316GlnfsTer5
NM_000314.8:c.947del
Pathogenic
This PTEN frameshift variant (L316Qfs*5) is classified as Pathogenic based on PVS1 (Very Strong LOF), PS3 (Strong functional evidence of damaging effect), PM2 (Supporting absence from population), PP5 (Supporting reputable source), and BP4 (Supporting benign computational evidence). The combination satisfies ACMG criteria for 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.947del
Protein Change
L316Qfs*5
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 316: L316P
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.947del
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
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
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
ClinVar reports other pathogenic variants at position 316: L316P
PM5 criterion applied.
Functional Summary
The PTEN L316Qfs*5 variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have demonstrated that such truncating mutations lead to oncogenic effects, including increased genome fragility and loss of chromosomal centromere association, supporting a damaging effect of this 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, the rule for PVS1 is: 'Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific'. The evidence for this variant shows: NM_000314.8:c.947del is a frameshift leading to a premature stop codon (L316Qfs*5) in PTEN, a gene where loss of function is a known disease mechanism, and the variant is not in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at the same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.' The evidence for this variant shows: it is a frameshift (L316Qfs*5), not the same amino acid change as a known pathogenic variant. Therefore, this criterion is not applied because the variant type does not match a PS1 scenario.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.' The evidence for this variant shows: there are no data on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: 'Strong Strength: Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: functional studies demonstrate that L316Qfs*5 abolishes PTEN phosphatase activity and leads to oncogenic effects. Therefore, this criterion is applied at Strong strength because established functional assays show a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.' The evidence for this variant shows: no case-control or proband specificity data are available. Therefore, this criterion is not applied due to lack of prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: Moderate Located in a mutational hot spot and/or critical and well-established functional domain defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3).' The evidence for this variant shows: codon 316 is outside defined PTEN hotspot regions. Therefore, this criterion is not applied because the variant is not located in a specified hotspot or domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.' The evidence for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare or absent in 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: PTEN-related conditions are autosomal dominant and no trans data are relevant. Therefore, this criterion is not applied because it pertains to recessive inheritance.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate Strength: 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 causing premature truncation, not an in-frame change or stop-loss. Therefore, this criterion is not applied because the variant type does not match PM4.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate Strength: Moderate 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: it is a frameshift, not a missense change. Therefore, this criterion is not applied because it is not a missense variant.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied due to lack of information.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting Strength: Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.' The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied because family segregation has not been assessed.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting Strength: Supporting 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: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence for this variant shows: in silico tools (SpliceAI score 0.01) show minimal impact. Therefore, this criterion is not applied because computational predictions do not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting Strength: 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 specific phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Strength: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: ClinVar (1 clinical laboratory) reports this variant as Pathogenic. Therefore, this criterion is applied at Supporting strength because a reputable database lists it as pathogenic without underlying data.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%).' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied because the frequency does not exceed the threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong Strength: Strong 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.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.' 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 Strength: Strong Lack of segregation in affected members of two or more families.' 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 Strength: Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease.' The evidence for this variant shows: it is 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 Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.' The evidence for this variant shows: no cis/trans data with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting Strength: Supporting In-frame deletions/insertions in a repetitive region without a known function.' The evidence for this variant shows: it is a frameshift deletion, not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak.' The evidence for this variant shows: SpliceAI score of 0.01 indicates minimal splicing impact. Therefore, this criterion is applied at Supporting strength because computational tools do not predict a damaging effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting Strength: Supporting Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular diagnosis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting Strength: Reputable source recently reports variant as benign, but the evidence is not available.' The evidence for this variant shows: no reputable source reports it as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting Strength: Supporting A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact.' The evidence for this variant shows: it is a frameshift in the coding sequence. Therefore, this criterion is not applied.