PTEN c.563_585del, p.Tyr188SerfsTer6
NM_000314.8:c.563_585del
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.563_585del
Protein Change
Y188Sfs*6
Location
Exon 6
(Exon 6 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 188: Y188C
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
ClinVar reports other pathogenic variants at position 188: Y188C
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 Y188Sfs*6 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have demonstrated that such truncating mutations are oncogenic, increasing genome fragility and disrupting PTEN's association with chromosomal centromeres.
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: 'c.563_585del (Y188Sfs*6) is a frameshift predicted to introduce a premature stop codon well upstream of the last exon, leading to NMD and loss of function; LOF is a known mechanism of PTEN-related disease'. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in PTEN predicted to result in loss of function per the PTEN decision tree.
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: 'Y188Sfs*6 is a frameshift resulting in a different amino acid sequence, not a missense matching an established pathogenic change'. Therefore, this criterion is not applied because the variant does not meet PS1.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Strong if de novo (both maternity and paternity confirmed) OR Very Strong for two proven/four assumed de novo events'. The evidence for this variant shows: 'No de novo data available'. Therefore, this criterion is not applied due to absence of de novo evidence.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule 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'. According to PTEN Pre-processing, the finding for PS3 is: 'The PTEN Y188Sfs*6 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway; functional studies demonstrate such truncating mutations are oncogenic and disrupt PTEN association with chromosomal centromeres'. The evidence for this variant shows these functional deficits. Therefore, this criterion is applied at Strong strength because well-established functional studies demonstrate a damaging effect for this variant.
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 prevalence significantly increased in affected vs controls'. The evidence for this variant shows: 'No case-control or proband-specificity data available'. Therefore, this criterion is not applied due to lack of prevalence data.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: Located in a mutational hotspot and/or critical functional domain (residues 90-94, 123-130, 166-168)'. The evidence for this variant shows: 'Y188 lies outside these 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 allele frequency in gnomAD or another large sequenced population'. The evidence for this variant shows: 'Not present in gnomAD or other population databases (MAF=0%)'. Therefore, this criterion is applied at Supporting strength because the variant is absent from control populations.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Moderate Strength: Detected in trans with a pathogenic variant for a recessive disorder'. The evidence for this variant shows: 'No trans or recessive case data available, and PTEN disorders are autosomal dominant'. 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: 'This is a frameshift leading to premature stop, not an in-frame indel'. 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: 'This is a frameshift 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: 'Moderate to Very Strong Strength depending on de novo assumptions'. The evidence for this variant shows: 'No de novo data 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 in multiple affected family members with 3-4 meioses'. The evidence for this variant shows: 'No segregation data 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 rate of benign missense variation'. The evidence for this variant shows: 'This is a frameshift variant'. 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 (e.g., REVEL >0.7)'. The evidence for this variant shows: 'SpliceAI score is 0.01; no computational evidence supports deleterious impact beyond frameshift'. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting Strength: Patient’s phenotype highly specific for a disease with single genetic etiology'. The evidence for this variant shows: 'No phenotype data provided'. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Strength: Reputable source reports variant as pathogenic without available evidence'. The evidence for this variant shows: 'No reputable database entry exists'. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: gnomAD Filtering allele frequency >0.00056'. The evidence for this variant shows: 'MAF 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: Allele frequency from 0.000043 up to 0.00056'. The evidence for this variant shows: 'MAF 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 in homozygous state in a healthy or PHTS-unaffected individual'. The evidence for this variant shows: 'No homozygous observations in healthy individuals'. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: Functional studies show 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: 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 for BP1 is: 'Supporting Strength: Missense variant in gene where primarily truncating variants cause disease'. The evidence for this variant shows: 'This 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 a pathogenic PTEN variant or in cis with multiple pathogenic variants'. The evidence for this variant shows: 'No cis/trans observations with other PTEN variants'. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting Strength: In-frame deletion/duplication in repeat region'. The evidence for this variant shows: 'This is a frameshift not in a repeat region'. 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 on gene or gene product'. The evidence for this variant shows: 'SpliceAI indicates minimal splicing impact but frameshift ensures impact; overall computational evidence is not supportive of benign effect'. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting Strength: 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: 'Supporting Strength: Reputable source reports variant as benign without evidence'. The evidence for this variant shows: '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 Strength: Synonymous or intronic variant with no splicing impact'. The evidence for this variant shows: 'This is a frameshift variant'. Therefore, this criterion is not applied.