PTEN c.159_160dup, p.Val54GlufsTer2
NM_000314.8:c.159_160dup
Pathogenic
This PTEN frameshift variant (V54Efs*2) results in early truncation and loss of function, supported by PVS1 Very Strong, PS3 Strong, and PM2 Supporting, with only BP4 Supporting as benign evidence, leading to a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
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.159_160dup
Protein Change
V54Efs*2
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 54 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.159_160dup
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
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 54 in gene PTEN
Functional Summary
The PTEN V54Efs*2 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 demonstrated that such truncating mutations are oncogenic, increasing genome fragility and disrupting chromosomal centromere association.
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 Use PTEN PVS1 decision tree." The evidence for this variant shows it is a frameshift (c.159_160dup, V54Efs*2) causing a null allele in PTEN, a gene where loss of function is a known disease mechanism and the variant does not occur in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific truncating variant rule.
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 a novel frameshift change with no matching known pathogenic amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "De novo occurrence confirmed by paternity and maternity." There is no information on de novo status for this variant. 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." The evidence for this variant shows functional studies demonstrating loss of PTEN phosphatase activity and oncogenic effect. Therefore, this criterion is applied at Strong strength because it meets the PTEN-specific functional evidence requirement.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared with controls or probands with specificity score ≥4." There are no case-control or proband specificity data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hotspot or critical functional domain (residues 90-94, 123-130, 166-168)." The variant at residue 54 is outside these motifs. 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 (allele frequency <0.00001 in gnomAD)." The evidence for this variant shows it is not present in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders with trans observations. 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, PM4 applies to in-frame indels causing protein length changes. This variant is a frameshift leading to truncation. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to novel missense changes at residues with known pathogenic missense variants. This is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 applies to assumed de novo occurrences without confirmation. No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to co-segregation with disease in multiple affected family members. No segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense rate. This is a frameshift variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 requires multiple lines of computational evidence supporting deleterious effect. Computational analyses show minimal splicing impact and no high REVEL score. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies when the phenotype is highly specific for a single gene disorder. No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when reputable sources report variant as pathogenic without evidence. The variant is not in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies to allele frequency >0.056%. The variant frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies to allele frequency 0.0043–0.056%. The variant frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to observation in homozygous state in unaffected individuals. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies to functional studies showing no damaging effect. Functional studies for this variant show damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation in multiple families. No segregation data are provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. This variant is truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 applies to observations in trans with pathogenic PTEN variants. No such data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." Computational analysis shows minimal predicted splicing impact (SpliceAI 0.03). Therefore, this criterion is applied at Supporting strength because computational data predict no impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when an alternate molecular basis for disease is present. No such alternate basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a variant is reported benign by a reputable source without evidence. No such report exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This variant is coding and frameshifting. Therefore, this criterion is not applied.