PTEN c.816_873del, p.His272GlnfsTer16
NM_000314.8:c.816_873del
Pathogenic
This frameshift variant in PTEN leads to loss-of-function, supported by PTEN-specific PVS1 Very Strong and PS3 Strong functional evidence, and is absent from controls (PM2 Supporting), meeting ACMG criteria for Pathogenic.
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.816_873del
Protein Change
H272Qfs*16
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 272: H272P
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.816_873del
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 272: H272P
PM5 criterion applied.
Functional Summary
The PTEN H272Qfs*16 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that such truncating mutations are oncogenic, as they increase genomic fragility and disrupt PTEN's association with chromosomal centromeres. This evidence supports a damaging effect of the variant.
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 Very Strong Strength is: "Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: c.816_873del (H272Qfs*16) is a frameshift resulting in a premature stop codon in a gene where loss of function is a known mechanism of disease and not located in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in PTEN consistent with the PTEN-specific PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 Strong Strength is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change..." The evidence for this variant shows a frameshift (H272Qfs*16) with no identical amino acid change previously established. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 Very Strong/Strong Strength relates to de novo occurrences with parental confirmation. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing and VCEP guidelines, the rule for PS3 Strong Strength is: "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 H272Qfs*16 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that such truncating mutations are oncogenic..." Therefore, PS3 is applied at Strong strength because well-established functional assays demonstrate a damaging effect consistent with VCEP PS3.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 relates to increased prevalence in affected individuals or case specificity scores. No case or prevalence data are available for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 Moderate Strength is: "Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94,123-130,166-168)." The evidence for this variant shows position H272 not within these defined critical motifs. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 Supporting Strength is: "Absent in population Databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows it is not found in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 relates to detection in trans with a pathogenic variant for recessive disorders. PTEN-related disease is autosomal dominant and no trans data are applicable. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 Moderate Strength concerns in-frame insertions/deletions in non-repeat regions or stop-loss variants. This variant is a frameshift leading to premature truncation, not an in-frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 Moderate Strength is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." This variant is a frameshift, not a missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 relates to assumed de novo occurrences without parental confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 concerns co-segregation in families. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 concerns missense variants in genes with low benign missense variation. This variant is a frameshift. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 Supporting Strength requires multiple computational lines supporting deleterious effect (e.g., REVEL>0.7 or strong splicing predictions). Computational data for this frameshift are not applicable. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 concerns phenotype specificity. No phenotypic data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 concerns reports by reputable databases. The variant is not found in ClinVar or similar. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 Stand Alone Strength is: "gnomAD filtering allele frequency >0.00056." The variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 Strong Strength concerns allele frequency 0.0043%-0.056%. The variant is absent from population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 concerns homozygous observations in unaffected individuals. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 Strong/Supporting Strength concerns functional studies showing no damaging effect. Functional studies show damaging effect for this variant. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 concerns lack of segregation in affected members. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 concerns missense variants in a gene where loss-of-function is the disease mechanism. This is a loss-of-function variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 concerns observations in trans with a pathogenic variant. Not applicable for this autosomal dominant variant. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 concerns in-frame indels in repeat regions. This variant is a frameshift. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 Supporting Strength requires computational evidence suggesting no impact. Not relevant for a frameshift. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 concerns alternate molecular basis for disease. No alternate cause is reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 concerns reputable databases reporting a benign variant. No such report exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 concerns synonymous or intronic variants without splicing impact. This variant is a frameshift. Therefore, BP7 is not applied.