PTEN c.368del, p.His123ProfsTer11
NM_000314.8:c.368del
Pathogenic
c.368del (H123Pfs*11) is a truncating LOF variant absent from population databases with strong functional evidence of damaging effect, fulfilling PVS1, PS3, and PM2, leading to 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.368del
Protein Change
H123Pfs*11
Location
Exon 5
(Exon 5 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 123: H123N, H123D, H123Y, H123R, H123Q
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.368del
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
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
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 123: H123N, H123D, H123Y, H123R, H123Q
PM5 criterion applied.
Functional Summary
The PTEN H123Pfs*11 variant is a truncating mutation that results in the loss of PTEN phosphatase function. This loss of function impairs the negative regulation of the PI3K/AKT pathway, contributing to oncogenic activity. Functional studies have demonstrated that such truncating mutations in PTEN lead to increased genome fragility and an inability to associate with chromosomal centromeres, supporting a damaging effect.
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: "Very Strong: Null variant (nonsense, frameshift, start codon, etc.) in a gene where LOF is a known mechanism of disease." The evidence shows that c.368del (H123Pfs*11) is a frameshift predicted to result in NMD in PTEN, a gene with haploinsufficiency. Therefore, PVS1 is applied at Very Strong strength because it is a truncating null variant in a gene where LOF causes disease.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change…" The evidence shows this is a frameshift variant, not a missense change recreating a known pathogenic amino acid substitution. Therefore, PS1 is not applied because the rule is not met.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Very Strong: Two proven or four assumed de novo observations…" There are no data on de novo occurrence for this variant. Therefore, PS2 is not applied due to lack of de novo evidence.
PS3
PS3 (Strong)
According to VCEP guidelines: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence shows functional studies demonstrate loss of PTEN phosphatase activity, genome instability, and failure to regulate PI3K/AKT pathway. Therefore, PS3 is applied at Strong strength because functional assays support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: Prevalence of variant in affected individuals is significantly increased compared with controls or probands with specificity score 4–15.5…" There are no case‐control data or proband specificity scores. Therefore, PS4 is not applied due to absence of evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate: Located in a mutational hotspot or critical functional domain (residues 90–94, 123–130)." The variant is a frameshift and not a missense change within these residues. Therefore, PM1 is not applied because the rule applies only to missense variants.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "Supporting: Absent in population databases present at <0.00001 allele frequency." The variant is absent from gnomAD, ESP, and 1000 Genomes. Therefore, PM2 is applied at Supporting strength because it is absent in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Moderate: For recessive disorders, detected in trans with a pathogenic variant…" PTEN disease is autosomal dominant and no trans observations exist. Therefore, PM3 is not applied due to non‐applicability in a dominant context.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Moderate: Protein length changes due to in-frame indels…" This variant is a frameshift truncation appropriately evaluated under PVS1. Therefore, PM4 is not applied because PVS1 covers null variants.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate: Missense change at a residue where a different missense change determined to be pathogenic has been seen." The variant is a frameshift, not a missense change. Therefore, PM5 is not applied because it does not meet the missense requirement.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong/Very Strong/Moderate: Assumed de novo occurrences…" No presumed de novo data are available. Therefore, PM6 is not applied due to lack of de novo evidence.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting: Co-segregation with disease in multiple affected family members (3–4 meioses)…" There are no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting: Missense variant in a gene with low rate of benign missense variation…" The variant is not a missense change. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting: Multiple lines of computational evidence support a deleterious effect…" The variant is a frameshift null change, and computational splicing predictions show minimal impact on splicing but are irrelevant to its LOF effect. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting: Patient’s phenotype is highly specific for a disease with single genetic etiology…" No phenotype data were provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting: Reputable source reports variant as pathogenic…" ClinVar classifies this variant as VUS, not (likely) pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "Stand Alone: Allele frequency >0.00056…" The variant is not frequent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: Allele frequency 0.000043–0.00056…" The variant frequency is zero. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: Observed homozygous in healthy…" No homozygous observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: Functional studies show no damaging effect…" Functional studies show damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: Lack of segregation in affected members…" No segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting: Missense variant in a gene where truncating variants are known mechanism…" The variant is truncating and not missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting: Observed in trans with pathogenic variant…" No such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting: In-frame indels in repetitive region…" The variant is a frameshift truncation. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting: Multiple lines of computational evidence suggest no impact…" Although splicing algorithms predict minimal impact, the variant causes LOF by frameshift. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting: Variant found with alternate molecular basis…" No alternate molecular basis reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "Supporting: Reputable source labels as benign…" ClinVar lists as VUS, not benign. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting: Synonymous or intronic variant…" The variant is not synonymous or intronic. Therefore, BP7 is not applied.