PTEN c.202del, p.Tyr68ThrfsTer31
NM_000314.8:c.202del
Pathogenic
The NM_000314.8:c.202del (Y68Tfs*31) variant results in a truncating frameshift in PTEN, leading to loss of function confirmed by functional studies, is absent from population databases, and meets PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting) per VCEP guidelines. The combined evidence supports 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.202del
Protein Change
Y68Tfs*31
Location
Exon 3
(Exon 3 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 68: Y68D, Y68H, Y68N, Y68S, Y68C
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.202del
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
ClinVar reports other pathogenic variants at position 68: Y68D, Y68H, Y68N, Y68S, Y68C
PM5 criterion applied.
Functional Summary
The PTEN Y68Tfs*31 variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have demonstrated that such truncating mutations are oncogenic, leading to increased genome fragility and an inability to associate with chromosomal centromeres.
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 a frameshift leading to a premature stop codon (Y68Tfs*31) in PTEN, a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a gene with LOF disease mechanism.
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...". The evidence for this variant shows it is a novel frameshift (not a known missense change). Therefore, this criterion is not applied because there is no matching amino acid change to a known pathogenic variant.
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...". There are no reported de novo observations for this variant. 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 PTEN pre-processing finding is: "The PTEN Y68Tfs*31 variant is a truncating mutation that results in the loss of PTEN phosphatase function... Functional studies have demonstrated that such truncating mutations are oncogenic." Therefore, this criterion is applied at Strong strength because functional studies show a damaging effect on PTEN activity.
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...". There is no case-level or cohort data for this variant. 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... (residues 90-94, 123-130)". The variant affects residue 68, which is outside defined critical domains. 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...". The evidence for this variant shows it is absent from gnomAD and other control databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder...". PTEN-related disorders are autosomal dominant and there is no evidence of this variant in trans 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: Moderate Protein length changes due to in-frame deletions/insertions...". The variant is a frameshift leading to truncation, 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 is: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic...". This variant is 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... de novo observations...". No presumed 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: "Supporting Strength: Supporting Co-segregation with disease in multiple affected family members...". No segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: Supporting Missense variant in a gene with low benign missense variation...". This variant is 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...". Computational tools (SpliceAI=0.03, no deleterious predictions) do not support a damaging effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Supporting Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.". No detailed phenotype is 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: Supporting Reputable source reports variant as pathogenic...". The variant is not found in ClinVar or other reputable databases. 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...". The variant 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 Allele frequency from 0.000043 up to 0.00056...". The variant is absent from population databases. 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 individual...". No homozygous observations in healthy individuals are reported. 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...". Functional studies show damaging effect, not lack thereof. 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.". No segregation or lack thereof is reported. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Supporting Missense variant in a gene for which primarily truncating variants cause disease...". This is a truncating variant, not 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 PTEN variant...". No such observations are reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: Supporting In-frame deletions/insertions in a repetitive region without a known function.". This variant is a frameshift, not an in-frame change in a repeat. 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...". While computational data show minimal splicing impact, the variant’s truncating nature supersedes computational benign predictions. 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...". No alternate molecular basis 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 Strength: Supporting Reputable source recently reports variant as benign or likely 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 Strength: Supporting A synonymous or intronic variant at or beyond +7/-21...". This variant is exonic frameshift. Therefore, this criterion is not applied.