PTEN c.1026+2T>G, p.Splice_Site
NM_000314.8:c.1026+2T>G
COSMIC ID: COSM41123
Pathogenic
This canonical +2 splice donor site variant in PTEN is predicted to lead to loss of function, absent from population databases, supported by computational splicing evidence, and reported as pathogenic by reputable sources. Under VCEP guidelines, PVS1 Very Strong plus additional supporting criteria (PM2, PP3, PP5) yield a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PM2
PP3
PP5
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.1026+2T>G
Protein Change
Splice
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM41123
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.1026+2T>G
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
1 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
2 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change affects a donor splice site in intron 8 of the PTEN gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Cowden or Cowden-like syndrome (PMID: 21194675, 28677221). ClinVar contains an entry for this variant (Variation ID: 428197). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PTEN protein in which other variant(s) (Deletion of Exon 9) have been determined to be pathogenic (PMID: 10468583, 10866658, 11035045, 12297295, 24905788, 25336918, 25448482). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 6.34
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 Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: a +2 canonical splice donor site change in PTEN, not in the last exon, predicted to cause loss of function in a gene where LOF is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because a canonical ±1/2 splice site variant meets the VCEP PVS1 decision tree for a null effect.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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. Modification Type: Disease-specific". The evidence for this variant shows: no previously established pathogenic variant at the exact +2 splice position. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: 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. Modification Type: Strength". The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing findings, the rule/finding for PS3 is: "Functional studies (PS3): The variant has not been functionally characterized.". The evidence for this variant shows: no in vitro or in vivo functional assays have been reported. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 (Strong) is: "Probands with specificity score 4-15.5 OR the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Modification Type: Strength". The evidence for this variant shows: no case or case-control 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 Strength: 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). Modification Type: Disease-specific". The evidence for this variant shows: it affects a splice site outside coding domain motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: 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%). Modification Type: Disease-specific". The evidence for this variant shows: allele frequency = 0% in gnomAD. Therefore, this criterion is applied at Supporting strength.
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 recessive gene.". The evidence for this variant shows: PTEN is not a recessive gene and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Modification Type: Disease-specific". The evidence for this variant shows: it is a splice site variant, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before... Modification Type: Disease-specific". 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: "Strong/Very Strong: presumed de novo occurrences without full confirmation... Modification Type: Strength". The evidence for this variant shows: no 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 Strength: Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. Modification Type: Disease-specific". The evidence for this variant shows: no family 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: 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 a splice site variant. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak. Modification Type: Disease-specific". The evidence for this variant shows: SpliceAI predicts donor site loss with a score of 0.99. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: 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 detailed phenotypic data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Supporting Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: ClinVar reports it as Pathogenic in 2 submissions and Likely pathogenic in 1. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%).". The evidence for this variant shows: allele frequency = 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%). Modification Type: Disease-specific". The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual...". The evidence for this variant shows: no such observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function...". The evidence for this variant shows: no functional assays demonstrating lack of impact. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Strong Lack of segregation in affected members of two or more families.". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Supporting Missense variant in a gene for which primarily truncating variants cause disease.". The evidence for this variant shows: it is a splice site variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: 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. Modification Type: Disease-specific". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: Supporting In-frame deletions/insertions in repeat regions without known functional impact.". The evidence for this variant shows: it is a splice site variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak.". The evidence for this variant shows: SpliceAI predicts a damaging effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Supporting Variant found in a case with an alternate molecular basis for disease...". The evidence for this variant shows: no alternate molecular explanation provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: Supporting Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: 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. Modification Type: Disease-specific". The evidence for this variant shows: it is at +2, within the canonical splice site. Therefore, this criterion is not applied.