PTEN c.894_895delinsC, p.Gln298HisfsTer9
NM_000314.8:c.894_895delinsC
Pathogenic
The PTEN Q298Hfs*9 frameshift variant is classified as Pathogenic based on Very Strong PVS1 (null variant in a gene with LOF mechanism), Strong PS3 (functional studies demonstrating damaging effect), and Supporting PM2 (absent from population databases), consistent with PTEN VCEP guidelines.
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.894_895delinsC
Protein Change
Q298Hfs*9
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 298 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.894_895delinsC
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
No evidence of other pathogenic variants at position 298 in gene PTEN
Functional Summary
The PTEN Q298Hfs*9 variant is a truncating mutation that results in a loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that such truncating mutations in PTEN are oncogenic, increasing genome fragility and impairing chromosomal centromere association.
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: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: it is a frameshift (Q298Hfs*9) predicted to cause a premature stop codon in an exon not in the last exon, resulting in loss-of-function in PTEN. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for null variants where loss-of-function is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change...". The evidence shows: there is no previously reported variant resulting in the same amino acid change at Q298. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations..." and "Strong Strength: De novo (both maternity and paternity confirmed)...". The evidence shows: no de novo inheritance data available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing: "The PTEN Q298Hfs*9 variant is a truncating mutation that results in a loss of PTEN phosphatase function...Functional studies have demonstrated that such truncating mutations in PTEN are oncogenic, increasing genome fragility and impairing chromosomal centromere association." The evidence for this variant shows: well-established in vitro and in vivo functional assays demonstrate damaging effect on PTEN activity. Therefore, this criterion is applied at Strong strength because functional studies support a damaging effect on the gene product.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Very Strong Strength: Probands with specificity score ≥16..." and lower levels. The evidence shows: there is no case series or statistical enrichment data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate Strength: Located in a mutational hot spot and/or critical and well-established functional domain... residues in catalytic motifs: 90-94, 123-130, 166-168." The evidence shows: Q298 is not within these defined motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population." The evidence for this variant shows: absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases below the specified threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "For recessive disorders, detected in trans with a pathogenic variant...". The evidence shows: PTEN-related disease is haploinsufficient, not recessive, and no in trans data are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region...". The evidence shows: this 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: "Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic...". The evidence shows: 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: "Very Strong/Strong/Moderate Strength: Based on assumed de novo occurrences...". The evidence shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong/Moderate/Supporting Strength: Co-segregation with disease in multiple affected family members...". The evidence shows: no segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Strength: Missense variant in a gene that has a low rate of benign missense variation...". The evidence shows: this is a frameshift variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect...". The evidence shows: SpliceAI score is minimal (0.02) and not predictive of splicing impact, and computational tools do not add support beyond known LoF. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Strength: Phenotype specific for disease with single genetic etiology...". The evidence shows: no detailed phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Strength: Variant reported as pathogenic by a reputable source...". The evidence shows: not present in ClinVar or other reputable database. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "Stand Alone Strength: gnomAD Filtering allele frequency >0.00056 (0.056%)". The evidence shows: variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: Allele frequency from 0.000043 up to 0.00056...". The evidence shows: variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong/Supporting Strength: Observed in the homozygous state in a healthy individual...". The evidence shows: no homozygous observations in unaffected individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong/Supporting Strength: Well-established functional studies show no damaging effect...". The evidence shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong/Supporting Strength: Lack of segregation in affected members...". The evidence shows: no segregation data indicating lack of segregation. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Strength: Missense variant in gene where only truncating variants cause disease...". The evidence shows: this is a truncating variant, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Observed in trans with a pathogenic PTEN variant...". The evidence shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Strength: In-frame indels in repetitive regions with no predicted functional impact...". The evidence shows: this is a frameshift, not in-frame. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Multiple lines of computational evidence suggest no impact...". The evidence shows: computational tools do not add benign support for a truncating variant already shown to be damaging. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Strength: Variant found in a case with an alternate molecular basis for disease...". The evidence shows: no alternate molecular diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting Strength: A variant reported as benign by a reputable source without available evidence...". The evidence shows: no such benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: A synonymous or intronic variant at or beyond +7/-21 with no splicing impact...". The evidence shows: variant is a frameshift, not synonymous or intronic. Therefore, this criterion is not applied.