PTEN c.417_429delinsT, p.Leu139_Gly143delinsPhe
NM_000314.8:c.417_429delinsT
Variant of Uncertain Significance (VUS)
This in-frame deletion–insertion variant in PTEN is absent from population databases (PM2 Supporting) but lacks functional, segregation, case, and computational evidence for pathogenicity or benign impact, resulting in a classification of VUS.
ACMG/AMP Criteria Applied
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.417_429delinsT
Protein Change
L139_G143delinsF
Location
Exon 5
(Exon 5 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.417_429delinsT
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 is applied only to null variants per the PTEN PVS1 decision tree. The evidence for this variant shows an in-frame deletion–insertion (L139_G143delinsF), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 requires the same amino acid change as a previously established pathogenic variant or a different variant at the same nucleotide as a known pathogenic splice variant. The evidence for this variant shows a novel in-frame delins not previously reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires de novo occurrence with confirmed paternity and maternity in an affected individual. No parental or de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN pre-processing, functional studies for this variant have not been performed. The evidence for this variant shows no functional characterization. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires an increased prevalence in affected individuals or specific proband scoring. No clinical or case data are available for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants located in critical PTEN catalytic motifs (residues 90–94, 123–130, 166–168). The evidence for this variant shows it affects residues 139–143, outside these motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 (Supporting) is: "Absent in population databases or present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows it is not present in gnomAD (0% frequency). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive disorders and requires trans observations with pathogenic variants. PTEN-associated disease is autosomal dominant, and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, PM4 (Moderate) applies to in-frame indels impacting PTEN catalytic motifs. The evidence for this variant shows an in-frame delins at residues 139–143, outside of catalytic motifs. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 (Moderate) requires a novel missense change at a residue with a different known pathogenic missense change. This variant is an in-frame delins, not a missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 requires presumed de novo occurrence without confirmation. No parental data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation in affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG, PP2 applies to missense variants in genes with low benign variation and common missense mechanism. This variant is an in-frame delins. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 requires multiple computational predictions supporting deleterious effect. SpliceAI predicts acceptor gain at 0.41 (below significant threshold) and no strong in silico evidence of deleterious impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG, PP4 requires a highly specific phenotype. No clinical phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG, PP5 requires a reputable source asserting pathogenicity. This variant is not in ClinVar or other databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 (Stand Alone) applies to allele frequency >0.056% in gnomAD. The evidence shows 0% frequency. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires allele frequency between 0.0043% and 0.056%. The variant is absent (0%). Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 relies on homozygous observations in healthy individuals. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well-established functional studies showing no damaging effect. No functional data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected family members. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG, BP1 applies to missense variants in genes where truncating variants are the mechanism. This is an in-frame delins. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 applies to observation in trans with a pathogenic PTEN variant. No such data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG, BP3 applies to in-frame indels in repetitive regions. This variant is not in a repetitive region. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires multiple computational lines suggesting no impact. Computational predictions are inconclusive. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies when an alternate molecular basis exists. No alternate diagnosis data are provided. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG, BP6 requires a reputable source classifying the variant as benign. No such source exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This variant is neither synonymous nor intronic. Therefore, BP7 is not applied.