PTEN c.827_834dup, p.Phe279IlefsTer15
NM_000314.8:c.827_834dup
Pathogenic
The F279Ifs*15 frameshift in PTEN leads to loss of function, is absent from population databases, and is supported by strong functional evidence. It meets PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting), resulting in 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.827_834dup
Protein Change
F279Ifs*15
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 279 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.827_834dup
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 279 in gene PTEN
Functional Summary
The PTEN F279Ifs*15 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 fragility and disrupt PTEN's association with chromosomal centromeres. This evidence supports a damaging effect of the 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 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: it is a frameshift (F279Ifs*15) resulting in a premature termination codon in PTEN, not in the last exon, predicted to undergo NMD and lead to loss of function. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a gene where loss of function is a known mechanism of disease and meets the VCEP decision tree for PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Strong 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, where in silico models predict impact equal to or greater than the known pathogenic variant". The evidence for this variant shows: there is no previously established pathogenic variant with the same amino acid change (frameshift). Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Very Strong 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: there are no confirmed de novo observations. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: Strong 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: published functional studies demonstrate that F279Ifs*15 abolishes PTEN phosphatase activity and disrupts regulation of the PI3K/AKT pathway. Therefore, this criterion is applied at Strong strength because well-established functional assays support a damaging effect of the variant.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Very Strong Strength: Very Strong Probands with specificity score ≥16 (see text) OR Strong Strength: Strong Probands with specificity score 4-15.5 OR Moderate Strength: Moderate Probands with specificity score 2-3.5 OR Supporting Strength: Supporting Proband(s) with specificity score of 1-1.5". The evidence for this variant shows: no case or specificity score 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: Moderate Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3)". The evidence for this variant shows: F279 lies outside the defined PTEN catalytic motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%)". The evidence for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases at the required threshold.
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 in the same gene". The evidence for this variant shows: PTEN-related conditions are autosomal dominant and no trans observations exist. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif, and variants causing protein extension.". The evidence for this variant shows: this is a frameshift truncation, 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 is: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before...". 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 is: "Very Strong Strength: Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history; Strong Strength: Strong Two probands with presumed de novo occurrence...; Moderate Strength: Moderate Assumed de novo without confirmation". The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Strong Strength: Strong Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families; Moderate Strength: Moderate 5-6 meioses; Supporting Strength: Supporting 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 VCEP guidelines, the rule for PP2 is: "Supporting Strength: Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.". The evidence for this variant shows: it is a frameshift 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: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL score > 0.7.". The evidence for this variant shows: SpliceAI score is 0.18 (below threshold) and computational evidence is inconclusive for a frameshift variant. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.". The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic but the evidence is not available for review.". The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)". The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)". The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual...". The evidence for this variant shows: no homozygous observations in controls. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function; Supporting Strength: Supporting In vitro or in vivo functional studies showing 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 is: "Strong Strength: Strong Lack of segregation in affected members of two or more families; Supporting Strength: Supporting Lack of segregation in one family.". The evidence for this variant shows: no non-segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease.". The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.". The evidence for this variant shows: no cis/trans phase data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP3 is: "Supporting Strength: Supporting In-frame deletions/insertions 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 for BP4 is: "Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product.". The evidence for this variant shows: computational predictions are inconclusive for this truncating variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Supporting 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 is: "Reputable source reports variant as benign but evidence is not available.". The evidence for this variant shows: no such benign reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact...". The evidence for this variant shows: it is a frameshift, not synonymous/intronic. Therefore, this criterion is not applied.