PTEN c.779_782del, p.Lys260ArgfsTer5
NM_000314.8:c.779_782del
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.779_782del
Protein Change
K260Rfs*5
Location
Exon 7
(Exon 7 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 260 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
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 260 in gene PTEN
Functional Studies
Summary
The PTEN K260Rfs*5 variant is a truncating mutation that results in a loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have shown that expression of PTEN truncation mutations in mouse embryonic fibroblasts is oncogenic and increases genome fragility due to impaired chromosomal centromere association. This evidence supports a damaging effect of the variant.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
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 truncating mutation c.779_782delAACA resulting in premature truncation (K260Rfs*5) in PTEN, a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP rule.
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. Modification Type: Disease-specific'. The evidence for this variant shows a frameshift (K260Rfs*5), not the same amino acid change as any known pathogenic variant. Therefore, PS1 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 OR '**Strong Strength**: Strong De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. Modification Type: Strength'. There are no de novo data available for this variant. Therefore, PS2 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. Modification Type: Disease-specific'. The evidence for this variant shows that functional studies of PTEN K260Rfs*5 demonstrate loss of phosphatase activity, oncogenic transformation in mouse embryonic fibroblasts, and increased genome fragility. Therefore, PS3 is applied at Strong strength because it meets the VCEP rule.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: '**Strong Strength**: Strong Probands with specificity score 4-15.5 OR significant increased prevalence in cases versus controls. Modification Type: Strength'. No case-level data or specificity scores are available for this variant. Therefore, PS4 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 (residues 90-94, 123-130, 166-168). Modification Type: Disease-specific'. The evidence shows the variant affects residue 260, outside defined catalytic motifs. Therefore, PM1 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. Modification Type: Disease-specific'. The evidence shows the variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because it meets the VCEP rule.
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.' The evidence shows PTEN-related disease is autosomal dominant and no trans data exist. Therefore, PM3 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. Modification Type: Disease-specific'. The evidence shows the variant is a frameshift resulting in truncation, not an in-frame change. Therefore, PM4 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 has been seen before. Modification Type: Disease-specific'. The evidence shows the variant is a frameshift, not a missense change. Therefore, PM5 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 OR '**Strong Strength**: Strong Two probands with presumed de novo occurrence. Modification Type: Strength'. No presumed or proven de novo data are available. Therefore, PM6 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. Modification Type: Strength'. There is no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence shows the variant is a frameshift, not missense. Therefore, PP2 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. SpliceAl and VarSeak concordance OR REVEL > 0.7. Modification Type: Disease-specific'. The evidence shows SpliceAI max score 0.05, below threshold. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype is highly specific for a disease with a single genetic etiology.' No phenotype information is provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic.' The evidence shows the variant is not present in ClinVar or other databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: gnomAD Filtering allele frequency >0.00056 (0.056%). Modification Type: Disease-specific'. The variant has MAF=0%. Therefore, BA1 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 up to 0.00056; '**Supporting Strength**: Supporting allele frequency from 0.0000043 up to 0.000043. Modification Type: Disease-specific'. The variant has MAF=0%. Therefore, BS1 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 healthy or PHTS-unaffected individual; '**Supporting Strength**: Supporting Two homozygous observations. Modification Type: Disease-specific'. No homozygous observations are reported. Therefore, BS2 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. Modification Type: Disease-specific'. The evidence shows damaging functional effects. Therefore, BS3 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. Modification Type: Disease-specific'. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where truncating variants are a common mechanism of disease.' The evidence shows a truncating variant, not missense. Therefore, BP1 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. Modification Type: Disease-specific'. No such observations are reported. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive region without known function.' The variant is frameshift, not in-frame. Therefore, BP3 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. Modification Type: Disease-specific'. Although computational tools predict no splicing impact, this is overridden by PVS1. Therefore, BP4 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.' No alternate molecular basis is reported. Therefore, BP5 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.' No such report exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: '**Supporting Strength**: Supporting A synonymous or intronic variant at or beyond +7/-21 for which splicing algorithms predict no impact.' The variant is a frameshift, not synonymous or intronic. Therefore, BP7 is not applied.