PTEN c.309del, p.Cys105ValfsTer8
NM_000314.8:c.309del
COSM7346068
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Likely Pathogenic
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
1 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.309del
Protein Change
C105Vfs*8
Location
Exon 5
(Exon 5 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 105: C105R, C105F, C105Y
Alternate Identifiers
COSM7346068
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
Likely Pathogenic
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (1 clinical laboratories).
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 105: C105R, C105F, C105Y
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The PTEN C105Vfs*8 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 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 frameshift (c.309del) leading to premature truncation (C105Vfs*8) in PTEN, a gene where loss‐of‐function is a known mechanism of disease and the variant 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 a null variant.
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...'. The evidence for this variant shows a frameshift altering the amino acid sequence (not the same amino acid change as any known pathogenic 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...'. There is no de novo inheritance information available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing, the 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 that PTEN C105Vfs*8 leads to loss of phosphatase function, is oncogenic in mouse embryonic fibroblasts, and increases genomic fragility. Therefore, this criterion is applied at Strong strength because the functional studies meet PTEN-specific PS3 requirements.
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'. There is no case-control or proband specificity data provided. 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 functional domain (residues 90-94, 123-130, 166-168)'. The frameshift at codon 105 is outside of these specified critical residues. 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 (0.001%) allele frequency in gnomAD'. The evidence for this variant shows a 0% allele frequency in gnomAD and other population databases. 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'. There is no information on trans configuration with another variant. 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 or stop-loss'. This variant causes an out-of-frame truncation rather than an in-frame alteration. 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 a residue with another known pathogenic missense'. 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: 'Strong/Moderate: Assumed de novo without confirmation of paternity/maternity'. No de novo information is available. 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'. 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 benign variation where missense is common mechanism'. This variant is a frameshift. 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'. Computational tools are not predictive for frameshift variants, and no deleterious missense/splice predictions apply. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting Strength: Phenotype highly specific for a disease with single genetic etiology'. No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Strength: Reputable source recently reports variant as pathogenic'. The evidence for this variant shows ClinVar entries as Likely Pathogenic (3 labs) and Pathogenic (1 lab). Therefore, this criterion is applied at Supporting strength because reputable clinical laboratories report pathogenicity.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: allele frequency >0.056%'. The 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: allele frequency 0.0043%-0.056%'. The 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: Observed homozygous in healthy individuals'. No such observations exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong: functional studies show no damaging effect'. Functional studies show damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected members of two or more families'. No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting: Missense in a gene where only LOF causes disease'. The variant is a LOF frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Supporting: Observed in trans with a pathogenic PTEN variant'. No such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting: In-frame indel in a repetitive region without functional domain'. The variant is out-of-frame. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting: computational evidence suggests no impact'. This frameshift variant is clearly impactful; computational splice predictions are irrelevant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting: Variant found in a case with alternate molecular basis'. No such alternate diagnosis 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: Reputable source reports benign'. No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting: Synonymous or intronic variant with no splicing impact'. This is a frameshift variant. Therefore, this criterion is not applied.