PTEN c.348del, p.Asp116GlufsTer18
NM_000314.8:c.348del
COSMIC ID: COSM5841
Pathogenic
This legacy system is being phased out as Project HERA V3 is rolled out.
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.348del
Protein Change
D116Efs*18
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 116 in gene PTEN
Alternate Identifiers
COSM5841
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.348del
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 116 in gene PTEN
Functional Summary
The PTEN D116Efs*18 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 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/finding for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: c.348del causes a frameshift (p.D116Efs*18) resulting in loss of PTEN function, in a gene where loss-of-function is a known mechanism and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for null variants.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS1 is: "Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: there is no previously established pathogenic variant resulting in the same amino acid change at codon 116. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding 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." The evidence for this variant shows: no de novo status or parental confirmation data are available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule/finding for PS3 is: "Strong Strength: 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 the D116Efs*18 truncation abolishes PTEN phosphatase function, leading to oncogenic activation. Therefore, this criterion is applied at Strong strength because PTEN-specific functional data meet PS3 requirements.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS4 is: "Strong Strength: Probands with specificity score 4–15.5 OR increased prevalence in affected vs. controls." The evidence for this variant shows: no case-control data or specificity scores are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM1 is: "Moderate Strength: Located in a mutational hotspot or critical functional domain (residues 90–94, 123–130, 166–168)." The evidence for this variant shows: codon 116 is outside these defined catalytic motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule/finding for PM2 is: "Supporting Strength: Absent in population databases or present at <0.001% allele frequency." The evidence for this variant shows: it is not found in gnomAD or other large population databases (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, the rule/finding for PM3 is: "Moderate Strength: Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: PTEN is haploinsufficient and no trans observations apply. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM4 is: "Moderate Strength: Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: c.348del is a frameshift leading to premature termination, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM5 is: "Moderate Strength: Different missense change at an amino acid where a pathogenic missense has been seen." The evidence for this variant shows: it is a frameshift, not a missense at the same residue. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM6 is: "Very Strong Strength: Two proven or four assumed de novo observations or one proven + two assumed de novo." The evidence for this variant shows: no unconfirmed de novo observations are reported. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP1 is: "Supporting Strength: Co-segregation with disease in multiple affected family members (3–4 meioses)." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP2 is: "Supporting Strength: Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: in silico tools (SpliceAI, REVEL) predict no splicing or missense impact but this is a truncating variant. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP4 is: "Supporting Strength: Patient’s phenotype is highly specific for a disorder with a single genetic etiology." The evidence for this variant shows: no detailed phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: "Supporting Strength: Reputable source classifies variant as pathogenic without primary evidence." The evidence for this variant shows: no ClinVar or other reputable source record. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BA1 is: "Stand Alone Strength: 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/finding for BS1 is: "Strong Strength: 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/finding for BS2 is: "Strong Strength: Observed homozygous in healthy individual(s)." 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/finding for BS3 is: "Strong Strength: Well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies show damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS4 is: "Strong Strength: 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/finding for BP1 is: "Supporting Strength: 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/finding for BP2 is: "Supporting Strength: Observed in trans with a pathogenic PTEN variant." The evidence for this variant shows: no trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP3 is: "Supporting Strength: In-frame indels in a repetitive region." The evidence for this variant shows: it 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/finding for BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: computational data are not relevant for truncating mechanism. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis." 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/finding for BP6 is: "Supporting Strength: Variant classified as benign by a reputable source without evidence." The evidence for this variant shows: no such classification exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP7 is: "Supporting Strength: Synonymous or intronic variant with no splicing impact." The evidence for this variant shows: it is a frameshift in coding region. Therefore, this criterion is not applied.