PTEN c.127G>T, p.Glu43Ter
NM_000314.8:c.127G>T
COSMIC ID: COSM921064
Pathogenic
This early truncating variant in PTEN (p.Glu43*) is absent from population databases, predicted deleterious by multiple lines of computational and splicing analyses (PP3), supported by functional assay data at Moderate strength (PS3), and fits the LOF mechanism with PVS1 at Very Strong. Additional supporting evidence from ClinVar assertions (PP5) and absence in controls (PM2) lead to a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP3
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.127G>T
Protein Change
E43*
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM921064
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.127G>T
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 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant has not been reported in the literature in individuals with PTEN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu43*) in the PTEN gene. It is expected to result in an absent or disrupted protein product.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 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
Functional Studies & Therapeutic Relevance
Functional Summary
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Neutral: Show all
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: NM_000314.8:c.127G>T is a nonsense change (p.Glu43*) 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 PVS1 decision tree for a canonical null variant leading to LOF.
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: p.Glu43* is not identical to any previously established pathogenic amino acid change at this residue nor is it a recapitulation of a known splice 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...". The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "PS3_Moderate evidence added based on high-confidence functional score (-3.5729) < threshold (-1.11)". The evidence for this variant shows: a validated functional assay reports phosphatase activity per Mighell et al. 2018 of -3.5729, exceeding the damaging threshold. Therefore, this criterion is applied at Moderate strength because the PTEN-specific functional score meets the PS3_moderate threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Probands with specificity score 4-15.5 OR increased prevalence in cases vs controls...". The evidence for this variant shows: no case-control or proband-specific 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 evidence for this variant shows: p.Glu43* lies outside the defined catalytic motifs of PTEN. 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...". The evidence for this variant shows: it is absent from gnomAD and other large population datasets. Therefore, this criterion is applied at Supporting strength because the allele frequency is below the disease-specific threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG, the rule for PM3 applies to recessive disorders requiring trans observations. The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans observations are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Protein length changes due to in-frame deletions/insertions...". The evidence for this variant shows: p.Glu43* is a nonsense variant, not an in-frame change. 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...". The evidence for this variant shows: it is a nonsense variant, 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: "Strong/Very Strong Strength: Assumed de novo observations without confirmation...". The evidence for this variant shows: no de novo or familial data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Strength: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed...". The evidence for this variant shows: no segregation data reported. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG, the rule for PP2 is: "Supporting Strength: Missense variant in a gene with low benign missense variation where missense is common mechanism...". The evidence for this variant shows: it is a nonsense change. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect... Splicing variants: Concordance of SpliceAI and VarSeak...". The evidence for this variant shows: SpliceAI predicts donor loss with a score of 0.53 supporting splicing impact, and other in silico tools show potential damage. Therefore, this criterion is applied at Supporting strength because computational evidence indicates a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG, the rule for PP4 is: "Phenotype specificity for a single genetic etiology...". The evidence for this variant shows: no patient phenotype data were provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG, the rule for PP5 is: "Supporting Strength: Reputable source recently reports variant as pathogenic, but evidence is not available to laboratory for independent evaluation". The evidence for this variant shows: ClinVar lists this variant as Pathogenic by three clinical laboratories without accessible primary data. Therefore, this criterion is applied at Supporting strength because a reputable database reports pathogenicity without underlying data.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: gnomAD allele frequency >0.00056...". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: gnomAD allele frequency 0.000043–0.00056...". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Observed homozygous in healthy individual...". The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Well-established functional studies show no damaging effect...". The evidence for this variant shows: functional assay indicates damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule 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 exist. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG, the rule for BP1 is: "Supporting Strength: Missense variant in gene where LOF is mechanism...". The evidence for this variant shows: p.Glu43* is a truncating variant. 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 pathogenic PTEN variant...". The evidence for this variant shows: no cis/trans data available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG, the rule for BP3 is: "Supporting Strength: In-frame indels in repetitive regions...". The evidence for this variant shows: p.Glu43* is a nonsense variant, 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...". The evidence for this variant shows: computational tools suggest deleterious effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Variant found in case with alternate molecular basis...". The evidence for this variant shows: no alternate genetic etiology reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG, the rule for BP6 is: "Supporting Strength: Reputable source reports variant as benign...". The evidence for this variant shows: no benign assertions in reputable sources. 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 at or beyond +7/-21 with no splicing impact...". The evidence for this variant shows: p.Glu43* is a nonsense coding variant. Therefore, this criterion is not applied.