PTEN c.170dup, p.Leu57PhefsTer6
NM_000314.8:c.170dup
COSMIC ID: COSM5000
Pathogenic
c.170dup (L57Ffs*6) in PTEN is a frameshift predicted to undergo NMD in a gene where loss of function is disease-causing. Functional studies (PS3), absence from population databases (PM2), and reputable database reports (PP5), together with PVS1 Very Strong, support a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
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.170dup
Protein Change
L57Ffs*6
Location
Exon 3
(Exon 3 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 57: L57W
Alternate Identifiers
COSM5000
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.170dup
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 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 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 57: L57W
PM5 criterion applied.
Functional Summary
The PTEN L57Ffs*6 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that such truncating mutations are oncogenic, increasing genomic fragility and disrupting PTEN's association with chromosomal centromeres.
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 Use PTEN PVS1 decision tree." The evidence for this variant shows: c.170dup causes a frameshift (L57Ffs*6) predicted to undergo NMD in a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because a null variant in PTEN meets the VCEP decision tree for PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change..." The evidence for this variant shows: it is a frameshift, not a missense change at the same amino acid. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS2 is: "Very Strong Two proven OR four assumed... de novo observations..." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines the rule for PS3 is: "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 L57Ffs*6 abolishes PTEN phosphatase function and is oncogenic. Therefore, this criterion is applied at Strong strength because well-established functional assays support damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS4 is: "Very Strong Probands with specificity score ≥16..." The evidence for this variant shows: no proband count or case‐control data. 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 functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: position L57 is outside these domains. 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 <0.001% allele frequency in gnomAD..." The evidence for this variant shows: not present in gnomAD or other control databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population datasets.
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 trans data. 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 indels or stop-loss variants..." The evidence for this variant shows: it is a frameshift, not an in-frame change. 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: it is a frameshift, not a missense change. 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 de novo observations..." 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 the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members..." The evidence for this variant shows: no 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, 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..." The evidence for this variant shows: no in silico predictions provided for missense or splicing impact relevant to LOF. 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 single genetic etiology..." The evidence for this variant shows: no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines the rule for PP5 is: "Supporting 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 lists this variant as Pathogenic by two laboratories. Therefore, this criterion is applied at Supporting strength because a reputable database reports pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BA1 is: "Stand Alone allele frequency >0.056%..." 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 allele frequency 0.0043%–0.056%..." 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 in homozygous state in healthy individual..." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS3 is: "Strong Well-established in vitro or in vivo functional studies shows 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 the rule for BS4 is: "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 Missense variant in a gene where only truncating variants cause disease..." The evidence for this variant shows: it is a truncating variant, not missense. 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..." 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 indels in repetitive regions..." The evidence for this variant shows: it is a frameshift, not in a repetitive 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 not relevant for a truncating LOF variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP5 is: "Supporting Variant found in a case with an alternate molecular basis for disease..." The evidence for this variant shows: no alternative molecular basis reported. 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..." The evidence for this variant shows: no reputable benign reports. 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 with no splicing impact..." The evidence for this variant shows: it is a frameshift coding variant. Therefore, this criterion is not applied.