PTEN c.125_143delinsGTGAAGGCGTATACAGGAG, p.Leu42_Asn48delinsArgGluGlyValTyrArgSer
NM_000314.8:c.125_143delinsGTGAAGGCGTATACAGGAG
Variant of Uncertain Significance (VUS)
This in-frame delins in PTEN is absent from population databases (PM2_Supporting) and computational data predict no impact (BP4_Supporting). No other criteria apply due to lack of functional, segregation, de novo, or case data. The variant remains classified as 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.125_143delinsGTGAAGGCGTATACAGGAG
Protein Change
L42_N48delinsREGVYRS
Location
Exon 2
(Exon 2 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.125_143delinsGTGAAGGCGTATACAGGAG
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, the rule for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows that it is an in-frame delins (L42_N48delinsREGVYRS) not predicted to result in loss of function or a null allele. Therefore, this criterion is not applied because the variant does not meet the definitions for a null variant under the PTEN PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant. Modification Type: Disease-specific". The evidence for this variant shows no known pathogenic variant resulting in the same amino acid change and no splicing comparisons. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations...; Strong Strength: De novo (both maternity and paternity confirmed)...". The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "Functional studies (PS3): The PTEN L42_N48delinsREGVYRS variant has not been functionally characterized." The evidence for this variant shows no published in vitro or in vivo functional assays. Therefore, this criterion is not applied because functional impact has not been demonstrated.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Very Strong Strength: Probands with specificity score ≥16; Strong Strength: specificity score 4–15.5 or increased prevalence in cases; Moderate Strength: score 2–3.5; Supporting Strength: score 1–1.5.". The evidence for this variant shows no case reports or prevalence data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3).". The evidence for this variant shows the delins affects residues 42-48, outside these motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).". The evidence for this variant shows a MAF of 0% in gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant in a gene where LOF is a known mechanism.". The evidence for this variant shows no data on trans configuration with another variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1).". The evidence for this variant shows an in-frame delins at residues 42-48, outside the catalytic motifs. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before, with BLOSUM62 score equal to or less than the known variant.". The evidence for this variant shows it is not a simple missense change and no such comparisons exist. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations; Strong Strength: Two probands with presumed de novo occurrence...; Moderate Strength: Assumed de novo without confirmation.". The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting to Strong Strength: Co-segregation with disease in multiple affected family members, depending on number of meioses.". The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.". The evidence for this variant shows it is an in-frame delins, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect (e.g., SpliceAI/VarSeak concordance or REVEL >0.7).". The evidence for this variant shows SpliceAI score of 0.2 and no consensus prediction of deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.". The evidence for this variant shows no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Reputable source reports variant as pathogenic or likely pathogenic without available evidence for independent evaluation.". The evidence for this variant shows it is not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: gnomAD filtering allele frequency >0.00056 (0.056%).". The evidence for this variant shows allele frequency of 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: gnomAD filtering allele frequency from 0.000043 up to 0.00056 (0.0043%–0.056%); Supporting Strength: allele frequency 0.0000043–0.000043.". The evidence for this variant shows allele frequency of 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Observed in the homozygous state in a healthy or PHTS-unaffected individual; Supporting Strength if two homozygotes without clinical data.". The evidence for this variant shows no homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Well-established functional studies show no damaging effect; Supporting Strength: in vitro/in vivo studies with phosphatase activity >0.". The evidence for this variant shows no functional data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Lack of segregation in affected members of two or more families; Supporting Strength: lack of segregation in one family.". The evidence for this variant shows no segregation analysis. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Missense variant in a gene where only truncating variants cause disease.". The evidence for this variant shows it is an in-frame indel and PTEN disease mechanism includes LOF rather than benign missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Observed in trans with a pathogenic or likely pathogenic PTEN variant or in cis with ≥3 observations with different pathogenic variants.". The evidence for this variant shows no phasing data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame deletions/insertions in a repetitive region without a known function.". The evidence for this variant shows it is in a non-repeat region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL <0.5.". The evidence for this variant shows SpliceAI predicts minimal impact (max score 0.2) and no other in silico predictors suggest deleterious effect. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis for disease.". The evidence for this variant shows no alternate molecular diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: Reputable source reports variant as benign without evidence.". The evidence for this variant shows no such report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: A synonymous or intronic variant with no splicing impact.". The evidence for this variant shows it is not synonymous or intronic. Therefore, this criterion is not applied.