PTEN c.184_192del, p.Lys62_His64del
NM_000314.8:c.184_192del
Variant of Uncertain Significance (VUS)
K62_H64del is an in-frame deletion outside PTEN catalytic motifs, absent from population databases, with no functional, segregation, or case-level evidence; only PM2_Supporting and BP4_Supporting apply, resulting in a classification of VUS.
ACMG/AMP Criteria Applied
PM2
BP4
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.184_192del
Protein Change
K62_H64del
Location
Exon 3
(Exon 3 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.184_192del
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PVS1 applies to null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism.' The evidence for this variant shows it is an in-frame deletion (K62_H64del), not predicted to produce a null allele. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' There is no known pathogenic variant resulting in K62_H64del. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' There are no de novo data for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing: 'The PTEN K62_H64del variant has not been functionally characterized.' There are no well-established functional studies showing a damaging effect. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS4: Prevalence in affected individuals is significantly increased compared to controls or proband specificity score ≥4.' There are no reported probands or case-control data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM1: Located in a mutational hotspot or critical functional domain (catalytic motifs 90-94, 123-130, 166-168).' The K62_H64del lies outside these motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: 'PM2 (Supporting): Absent in population databases present at <0.00001 allele frequency in gnomAD.' The variant is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PM3: Observed in trans with a pathogenic variant for recessive disorders.' PTEN-related disease is autosomal dominant and there is no evidence of trans observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM4: In-frame deletions/insertions impacting at least one residue in a catalytic motif.' The K62_H64del does not affect a catalytic motif. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' This variant is an in-frame deletion, not a missense change, and no pathogenic missense at these residues is reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM6: Assumed de novo without confirmation of paternity/maternity.' There are no de novo reports. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP1: Co-segregation with disease in multiple affected family members.' No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PP2: Missense variant in a gene with low rate of benign missense variation where missense is common mechanism.' This is an in-frame deletion, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP3: Multiple lines of computational evidence support a deleterious effect (REVEL >0.7 for missense or concordant splicing impact).' In silico tools (SpliceAI score 0.04) do not predict deleterious impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PP4: Patient’s phenotype highly specific for gene.' No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PP5: Variant reported as pathogenic by reputable source.' The variant is not in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BA1: Allele frequency >0.056% in gnomAD.' The allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS1: Allele frequency from 0.0043% up to 0.056%.' The allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS2: Observed in homozygous state in unaffected individual.' No such observations exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS3: Well-established in vitro or in vivo functional studies show no damaging effect.' No functional studies are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS4: Lack of segregation in affected members.' No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'BP1: Missense in a gene where only truncating variants cause disease.' This is an in-frame deletion, not missense, and LOF is known mechanism. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP2: Observed in trans with a pathogenic variant or in cis with multiple pathogenic variants.' No such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'BP3: In-frame indels in repetitive region without known function.' The region is not repetitive. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines: 'BP4: Multiple lines of computational evidence suggest no impact (SpliceAI and VarSeak concordance, REVEL <0.5 for missense).' SpliceAI score is 0.04 and other in silico predictions are unremarkable. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP5: 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: 'BP6: Reputable source reports variant as benign.' The variant is not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP7: Synonymous or intronic variant predicted no splicing impact.' This is an in-frame deletion, not synonymous/intronic. Therefore, this criterion is not applied.