PTEN c.918dup, p.Glu307ArgfsTer5
NM_000314.8:c.918dup
COSMIC ID: COSM10076122
Pathogenic
This frameshift variant, c.918dup (E307Rfs*5), produces a truncated PTEN protein and is absent from population databases. PTEN-specific decision tree supports PVS1 at Very Strong, in vitro/in vivo studies support PS3 at Strong, and absence from controls supports PM2 at Supporting. These combine to classify the variant as Pathogenic.
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.918dup
Protein Change
E307Rfs*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 307: E307Q
Alternate Identifiers
COSM10076122
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.918dup
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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
ClinVar reports other pathogenic variants at position 307: E307Q
PM5 criterion applied.
Functional Summary
The PTEN E307Rfs*5 variant is a truncating mutation that results in the production of C-terminally truncated PTEN proteins. Functional studies have shown that such truncating mutations lead to a loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Additionally, expression of PTEN truncation mutations in mouse embryonic fibroblasts has demonstrated oncogenic properties and increased genomic fragility due to the inability of truncated PTEN to associate with chromosomal centromeres. These findings support a damaging effect of the PTEN E307Rfs*5 variant.
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 Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific." The evidence for this variant shows a frameshift (NM_000314.8:c.918dup; E307Rfs*5) resulting in a truncated PTEN protein not in the last exon, consistent with loss-of-function. Therefore, this criterion is applied at Very Strong strength because a null variant in PTEN is a known mechanism of disease per the decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant..." The evidence for this variant shows a frameshift, not the same amino acid change as any known pathogenic missense or splicing variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." No de novo data are available for this case. 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 shows that E307Rfs*5 truncating mutations abolish PTEN phosphatase function, dysregulate PI3K/AKT signaling, and confer oncogenic properties in cellular assays and mouse models. Therefore, this criterion is applied at Strong strength because functional studies demonstrate a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Very Strong Strength: Probands with specificity score ≥16 OR Strong Strength: specificity score 4–15.5 or significant increase in prevalence in cases vs controls." No case count or prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: Located in a mutational hot spot and/or critical and well-established functional domain (residues 90–94, 123–130, 166–168)." The variant at residue 307 lies outside these domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent in population databases present at <0.00001 allele frequency in gnomAD or another large sequenced population." The evidence shows this variant is not observed in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it is absent from 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." No inheritance or trans data are available for this variant in PTEN. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." This variant is a frameshift leading to premature termination, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic 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, the rule for PM6 is: "Very Strong/Strong/Moderate Strength: Assumed de novo observations without confirmation." No de novo or family history data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong Strength: 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, the rule for PP2 is: "Supporting Strength: Missense variant in a gene with low rate of benign missense variation where missense is common disease mechanism." This is a loss-of-function variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect (REVEL>0.7 or splicing concordance)." In silico predictions (SpliceAI max score 0.01) do not support a deleterious effect on splicing or protein function. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No detailed phenotype or family history specific to PTEN-related syndrome is provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Reputable source reports variant as pathogenic without accessible evidence." This variant is not reported 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 is: "Stand Alone Strength: gnomAD Filtering allele frequency >0.00056." This variant’s frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: allele frequency from 0.000043 up to 0.00056." This variant’s frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong/Supporting Strength: Homozygous observations in healthy individuals." No homozygosity data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong/Supporting Strength: Well-established functional studies show no damaging effect." Functional studies for this variant demonstrate damaging effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong/Supporting Strength: Lack of segregation in affected members." No segregation evidence demonstrating lack of segregation is available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Missense variant in gene where loss-of-function is mechanism." This variant is a frameshift causing loss-of-function, not a benign missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Observed in trans with a pathogenic variant or multiple in cis." No such observations are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame indels in repetitive regions without functional impact." This variant is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact." SpliceAI predicts no significant splicing effect, but the variant’s frameshift nature overrides computational predictions. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis for disease." No alternate molecular basis 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 reports variant as benign without available evidence." No such benign assertion exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Synonymous or intronic variant with no predicted splicing impact." This variant is a frameshift. Therefore, this criterion is not applied.