PTEN c.125_143delinsGTGAAGGCCGTATACAGGAG, p.Leu42ArgfsTer10
NM_000314.8:c.125_143delinsGTGAAGGCCGTATACAGGAG
Pathogenic
This frameshift variant (L42Rfs*10) in PTEN leads to premature truncation, is absent from population databases, and has functional evidence of loss of phosphatase activity. It meets PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting), consistent with Pathogenic classification under ACMG/VCEP criteria.
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.125_143delinsGTGAAGGCCGTATACAGGAG
Protein Change
L42Rfs*10
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 42 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.125_143delinsGTGAAGGCCGTATACAGGAG
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
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
No evidence of other pathogenic variants at position 42 in gene PTEN
Functional Summary
The PTEN L42Rfs*10 variant is a truncating mutation that results in loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that such truncating mutations in PTEN are oncogenic, increasing genome fragility and impairing chromosomal centromere association. This evidence supports a damaging effect of the variant.
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, the rule for PVS1 is: "Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: it is a frameshift (L42Rfs*10) predicted to cause loss of function in PTEN, a gene where haploinsufficiency is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant leads to premature truncation consistent with the PTEN PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong 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." The evidence for this variant shows: there is no previously established pathogenic variant resulting in the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 is: "The PTEN L42Rfs*10 variant is a truncating mutation that results in loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that such truncating mutations in PTEN are oncogenic, increasing genome fragility and impairing chromosomal centromere association. This evidence supports a damaging effect of the variant." The evidence for this variant shows: functional studies demonstrate loss of PTEN function. Therefore, this criterion is applied at Strong strength because PTEN-specific functional data confirm a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls." The evidence for this variant shows: no case-level or proband data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate 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 affected residue (L42) is outside these critical motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting 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: it is not found in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases per VCEP thresholds.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Moderate Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans observations are provided. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate 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), and variants causing protein extension." The evidence for this variant shows: it is a frameshift deletion-insertion leading to a premature stop rather than an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant." The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." The evidence for this variant shows: no presumed de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed." The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting 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 not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak. Missense variants: REVEL score > 0.7." The evidence for this variant shows: in silico predictions are inconclusive with SpliceAI max score of 0.26. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting 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 or family history details are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source recently reports variant as pathogenic or likely pathogenic. No evidence provided." The evidence for this variant shows: no prior classifications found in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual." The evidence for this variant shows: no homozygous observations in unaffected individuals are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows: functional studies demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Missense variant in a gene for which loss of function is a known mechanism of disease." The evidence for this variant shows: the variant is truncating, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants." The evidence for this variant shows: no phase or cis/trans data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift deletion-insertion resulting in truncation. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak. Missense variants: REVEL scores < 0.5." The evidence for this variant shows: computational predictions are inconclusive. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN." The evidence for this variant shows: no alternate molecular basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Reputable source reports variant as benign. No evidence provided." The evidence for this variant shows: no benign classification found in reputable sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice." The evidence for this variant shows: it is not a synonymous or deep intronic variant. Therefore, this criterion is not applied.