PTEN c.79dup, p.Tyr27LeufsTer17
NM_000314.8:c.79dup
Pathogenic
The c.79dupT (Y27Lfs*17) variant in PTEN results in a truncating loss-of-function in a non-last exon, is absent from population databases, and has strong functional evidence of pathogenicity. Combined VCEP-guided PVS1 (Very Strong), PS3 (Strong), PM2 (Supporting) and PP5 (Supporting) 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.79dup
Protein Change
Y27Lfs*17
Location
Exon 1
(Exon 1 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 27: Y27N, Y27C, Y27S
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.79dup
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)
This sequence change creates a premature translational stop signal (p.Tyr27Leufs*17) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. For these reasons, this variant has been classified as Pathogenic.
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 27: Y27N, Y27C, Y27S
PM5 criterion applied.
Functional Summary
The PTEN Y27Lfs*17 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 genome fragility and disrupting chromosomal centromere association.
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: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree." The variant is a frameshift (c.79dupT) leading to truncation in a non‐last exon, causing loss of function in a gene where LOF is a known mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null variant in PTEN.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change…" The evidence shows this variant is a frameshift, not the same amino acid change as any known pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong De novo (both maternity and paternity confirmed) observation..." No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
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." According to PTEN Pre-processing note: "The PTEN Y27Lfs*17 variant is a truncating mutation that results in the loss of PTEN phosphatase function… Functional studies have shown that such truncating mutations are oncogenic." The evidence shows loss of phosphatase activity and oncogenic behavior. 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: "Strong The prevalence of the variant in affected individuals is significantly increased compared with controls…" No case‐level or statistical prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate Located in a mutational hot spot and/or critical functional domain: residues 90-94, 123-130, 166-168." The variant occurs at codon 27, outside those motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD…" The variant is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because it is not present in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM3 requires observation in trans with a pathogenic variant for recessive conditions. PTEN-related disease is autosomal dominant and no trans data are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate Protein length changes due to in‐frame deletions/insertions in a non‐repeat region…" This is a frameshift/truncation, not an in‐frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate Missense change at an amino acid residue where a different missense change…has been seen before." This variant is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Two probands with presumed de novo occurrence…" No presumed de novo data exist. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Co‐segregation with disease in multiple affected family members…" No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Missense variant in a gene with low benign missense variation…" This variant is not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Multiple lines of computational evidence support a deleterious effect…REVEL >0.7 or splicing models." In silico scores do not predict additional impact beyond the frameshift. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Patient’s phenotype or family history is highly specific…" No phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: "Supporting Reputable source recently reports variant as pathogenic, but evidence is not available to the laboratory…" ClinVar lists this variant as Pathogenic from one clinical laboratory. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)…" The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong gnomAD Filtering allele frequency 0.000043–0.00056…" The variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Observed in the homozygous state in a healthy individual…" No homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Well‐established functional studies show no damaging effect…" Functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Lack of segregation in affected members of two or more families…" No segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Missense variant in a gene where only LOF is mechanism…" This is a LOF frameshift variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Observed in trans with a pathogenic PTEN variant…" No such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting In‐frame indels in repetitive region…" This variant is a frameshift, not an in‐frame change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Multiple lines of computational evidence suggest no impact…" Computational data do not override clear LOF. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Variant found in a case with an alternate molecular basis…" No alternate diagnosis data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Reputable source reports variant as benign…" No such benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting A synonymous or intronic variant…predict no splicing impact…" This is a truncating variant. Therefore, this criterion is not applied.