PTEN c.480del, p.Arg161GlufsTer6
NM_000314.8:c.480del
Pathogenic
This frameshift variant leads to a truncated PTEN protein, resulting in loss of function. It meets PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting) criteria, consistent with a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
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.480del
Protein Change
R161Efs*6
Location
Exon 5
(Exon 5 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 161 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.480del
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 161 in gene PTEN
Functional Summary
The PTEN R161Efs*6 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 in PTEN are oncogenic, as they increase genomic instability and disrupt PTEN's association with chromosomal centromeres. Therefore, functional evidence supports 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 Very Strong is: "Null variant (nonsense, frameshift, ... single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows: c.480del causes R161Efs*6, a truncating frameshift predicted to undergo NMD and not located in the last exon. Therefore, this criterion is applied at Very Strong strength because it is a truncating variant in PTEN, where loss of function is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 Strong is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change...". The evidence for this variant shows: R161Efs*6 is a novel frameshift and does not match any known amino acid substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 Strong 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: no de novo occurrence data provided. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 Strong 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: PTEN R161Efs*6 truncating mutation abolishes phosphatase function and has been demonstrated in functional assays to disrupt PI3K/AKT regulation. Therefore, this criterion is applied at Strong strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 Strong is: "Probands with specificity score 4-15.5 or significant increased prevalence in affected individuals.". The evidence for this variant shows: no case-control or proband specificity data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 Moderate is: "Located in a mutational hot spot and/or critical functional domain residues 90-94, 123-130, 166-168.". The evidence for this variant shows: residue 161 is outside these defined hotspots. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 Supporting is: "Absent in population databases or present at <0.001% allele frequency in gnomAD.". The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 Moderate is: "Detected in trans with a pathogenic variant for recessive disorders.". The evidence for this variant shows: no observations of this variant in trans with another PTEN pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 Moderate is: "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 indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 Moderate is: "Missense change at a residue where a different pathogenic missense has been seen.". The evidence for this variant shows: this 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 Very Strong (or Strong/Moderate) is: "Assumed de novo without confirmation.". The evidence for this variant shows: no presumed de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 Supporting is: "Co-segregation with disease in multiple affected family members (3–4 meioses).". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 Supporting is: "Missense variant in a gene with low benign missense variation rate and where missense is a common mechanism.". The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 Supporting is: "Multiple lines of computational evidence support deleterious effect (SpliceAI, REVEL).". The evidence for this variant shows: SpliceAI score 0.01 and no deleterious predictions. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 Supporting is: "Patient’s phenotype is highly specific for a disease with single genetic etiology.". The evidence for this variant shows: no patient phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 Supporting is: "Reputable source reports variant as pathogenic.". The evidence for this variant shows: not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 Stand Alone is: "gnomAD Filtering allele frequency >0.00056.". The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 Strong is: "Allele frequency from 0.000043 up to 0.00056.". The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 Strong is: "Observed in the homozygous state in a 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 Strong is: "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, the rule for BS4 Strong is: "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 Supporting is: "Missense variant in gene where only truncating variants 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 Supporting is: "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 Supporting is: "In-frame indel in a repetitive region without a known function.". The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 Supporting is: "Computational evidence suggests no impact (SpliceAI, REVEL <0.5).". The evidence for this variant shows: SpliceAI minimal effect, but variant type is frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 Supporting is: "Variant found in a case with an alternate molecular basis for disease.". The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 Supporting is: "Reputable source reports variant as benign.". The evidence for this variant shows: not reported as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 Supporting is: "Silent or intronic variant with no splicing impact.". The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.