PTEN c.932_942del, p.Asn311IlefsTer10
NM_000314.8:c.932_942del
Pathogenic
This PTEN frameshift variant (c.932_942del, p.N311Ifs*10) meets PVS1_Very Strong (LoF), PS3_Strong (functional studies), and PM2_Supporting (absent from controls). 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.932_942del
Protein Change
N311Ifs*10
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 311 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.932_942del
Active Tracks
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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
No evidence of other pathogenic variants at position 311 in gene PTEN
Functional Summary
The PTEN N311Ifs*10 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 this truncation is oncogenic, increasing genome fragility and impairing PTEN's association 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 Use PTEN PVS1 decision tree." The evidence for this variant shows: c.932_942del is a frameshift causing a premature stop codon (N311Ifs*10) in PTEN, a gene in which loss‐of‐function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it is a null variant predicted to cause loss of PTEN function.
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 other pathogenic variant results in the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong 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: functional assays demonstrate complete loss of PTEN phosphatase activity and oncogenic effects of the truncation. Therefore, this criterion is applied at Strong strength because well-established studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Prevalence of the variant in affected individuals is significantly increased compared with controls or proband specificity score 4–15.5." The evidence for this variant shows: no case‐level or population enrichment data provided. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Located in a mutational hotspot or critical functional domain (residues 90–94, 123–130, 166–168)." The evidence for this variant shows: the frameshift begins at codon 311, outside defined hotspots. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent in population databases present at <0.00001 allele frequency." The evidence for this variant shows: not observed in gnomAD or other large controls. Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
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." The evidence for this variant shows: no recessive inheritance or trans observations reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Protein length changes due to in-frame indels in non-repeat regions or stop-loss variants." The evidence for this variant shows: this is a frameshift, 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 Missense change at a residue where another pathogenic missense has been seen." 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 is: "Moderate Assumed de novo without parental confirmation." The evidence for this variant shows: no de novo assumptions available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members (3–4 meioses)." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: this is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: computational tools are not applicable to frameshift impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Patient’s phenotype is 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 Reputable source reports variant as pathogenic." The evidence for this variant shows: not present in ClinVar or other databases. 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: allele frequency is zero. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Allele frequency from 0.000043 to 0.00056." The evidence for this variant shows: allele frequency is zero. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Observed in homozygous state in healthy individuals." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong 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 is: "Strong 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 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 is: "Supporting Observed in cis with a pathogenic PTEN variant." The evidence for this variant shows: no cis observations reported. 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 indels in repetitive regions without known function." The evidence for this variant shows: frameshift, not in-frame in repeats. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: computational prediction not relevant to frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Supporting 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 Reputable source reports variant as benign." The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Supporting Silent or intronic variant predicted to have no splicing impact." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.