PTEN c.521_522del, p.Tyr174CysfsTer5
NM_000314.8:c.521_522del
Pathogenic
This PTEN frameshift variant Y174Cfs*5 leads to loss of function, meeting PVS1 (Very Strong), PS3 (Strong) and PM2 (Supporting), fulfilling Pathogenic-1 classification for a pathogenic variant.
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.521_522del
Protein Change
Y174Cfs*5
Location
Exon 6
(Exon 6 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 174 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.521_522del
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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 174 in gene PTEN
Functional Summary
The PTEN Y174Cfs*5 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 shown that such truncating mutations are oncogenic, increasing genome fragility and disrupting chromosomal centromere association.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
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." The evidence for this variant shows: a frameshift (Y174Cfs*5) predicted to result in loss of function in PTEN, a gene where LOF is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because this is a null variant meeting the PTEN-specific PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change..." The evidence for this variant shows: no previously established PTEN pathogenic variant with the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 (Strong) is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: de novo status not assessed. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 (Strong) is: "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: studies demonstrate that Y174Cfs*5 abolishes PTEN phosphatase activity, dysregulates PI3K/AKT signaling, and is oncogenic. Therefore, this criterion is applied at Strong strength because robust functional data support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 (Strong) is: "Prevalence of the variant in affected individuals is significantly increased compared with controls or specificity score 4–15.5." The evidence for this variant shows: no case–control or proband data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 (Moderate) is: "Located in a mutational hot spot and/or critical and well-established functional domain including residues 90–94, 123–130, 166–168." The evidence for this variant shows: position Y174 is outside the defined 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 allele frequency in gnomAD." The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant 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." The evidence for this variant shows: no data on allelic configuration. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 (Moderate) is: "Protein length changes due to in-frame insertions/deletions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a frameshift, 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 (Moderate) is: "Missense change at a residue where a different missense change is pathogenic." The evidence for this variant shows: it 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 (Strong) is: "Two probands with presumed de novo occurrence without confirmation." 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 (Supporting) is: "Co-segregation with disease in multiple affected family members (3–4 meioses)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 (Supporting) is: "Missense variant in a gene with low benign missense rate where missense is a common mechanism." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 (Supporting) is: "Multiple lines of computational evidence support deleterious effect (REVEL>0.7 for missense)." The evidence for this variant shows: insufficient in silico data for splicing or missense. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Phenotype highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no patient phenotype 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 reports variant as pathogenic without available evidence." The evidence for this variant shows: no such report. Therefore, this criterion 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." The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 (Strong) is: "Allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 (Strong) is: "Observed in homozygous state in healthy individual." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 (Strong) is: "Well-established functional studies show no damaging effect." The evidence for this variant shows: 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 (Strong) is: "Lack of segregation in affected members of two 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: "Missense variant in gene where only truncating variants cause disease." The evidence for this variant shows: it is truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 (Supporting) is: "Observed in trans with a pathogenic PTEN variant." The evidence for this variant shows: no data on allelic phase. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertion/deletion in a repetitive region without functional impact." The evidence for this variant shows: frameshift outside repeat region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 (Supporting) is: "Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: no computational support for benign effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 (Supporting) is: "Variant found in case with alternate molecular basis for disease." The evidence for this variant shows: no such alternate basis. 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 without evidence." The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 (Supporting) is: "Synonymous or intronic variant with no splicing impact predicted." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.