PTEN c.1026+18T>C, p.?
NM_000314.8:c.1026+18T>C
Variant of Uncertain Significance (VUS)
The variant NM_000314.8:c.1026+18T>C in PTEN is intronic beyond canonical splice sites, absent from population databases (PM2 Supporting), and has no predicted impact on splicing (BP7 Supporting). No other criteria are met, resulting in a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP7
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+18T>C
Protein Change
?
Location
Exon 8
(Exon 8 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.1026+18T>C
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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.97
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PVS1 is: 'Use PTEN PVS1 decision tree' (Very Strong for null variants including canonical splice sites). The evidence for this variant shows it is intronic at +18, outside the canonical splice site positions +1 or +2. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant under the PTEN PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows no change in amino acid (intronic). Therefore, PS1 is not applied because there is no amino acid change matching a known pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 (Strong) is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows that de novo status is unknown. Therefore, PS2 is not applied due to lack of parental testing data.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN pre-processing, the finding for PS3 is: 'The PTEN 1026+18t>C variant has not been functionally characterized.' The evidence for this variant shows no functional assay data. Therefore, PS3 is not applied because there are no well-established functional studies demonstrating a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 (Supporting) is: 'Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5.' The evidence for this variant shows no case or proband data. Therefore, PS4 is not applied due to absence of affected individual data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM1 (Moderate) is: 'Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168).' The evidence for this variant shows it is intronic at +18, outside these domains. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM2 (Supporting) is: 'Absent in population Databases present at <0.00001 allele frequency in gnomAD.' The evidence for this variant shows it is absent from gnomAD and other large sequencing databases. Therefore, PM2 is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 relates to recessive disorders requiring trans observations with a pathogenic variant. The evidence for this variant shows no data on trans configuration or recessive inheritance. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM4 (Moderate) is: 'Protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants.' The evidence for this variant shows it is intronic with no protein length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM5 (Moderate) is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence for this variant shows no amino acid change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 (Strong) is: 'Assumed de novo occurrence without confirmation of paternity and maternity.' The evidence for this variant shows no de novo data. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PP1 (Supporting) is: 'Co-segregation with disease in multiple affected family members (3–4 meioses).' The evidence for this variant shows no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 (Supporting) is: 'Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism.' The evidence for this variant shows it is intronic. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PP3 (Supporting) is: 'Multiple lines of computational evidence support a deleterious effect.' The evidence for this variant shows computational predictors suggest no impact (SpliceAI = 0, CADD = 0.97). Therefore, PP3 is not applied because evidence does not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 (Supporting) is: '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, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 (Supporting) is: 'Reputable source recently reports variant as pathogenic or likely pathogenic.' The evidence for this variant shows no entries in ClinVar or similar. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BA1 (Stand Alone) is: 'gnomAD Filtering allele frequency >0.00056.' The evidence for this variant shows it is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS1 (Strong) is: 'allele frequency from 0.000043 up to 0.00056.' The evidence for this variant shows absence from databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS2 (Strong) is: 'Observed in the homozygous state in a healthy individual.' The evidence for this variant shows no homozygous observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS3 (Strong) is: 'Well-established in vitro or in vivo functional studies show no damaging effect.' The evidence for this variant shows no functional assays. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS4 (Strong) is: 'Lack of segregation in affected members of two or more families.' The evidence for this variant shows no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 (Supporting) is: 'Missense variant in a gene for which primarily loss-of-function is disease mechanism.' The evidence for this variant shows it is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BP2 (Supporting) is: 'Observed in trans with a pathogenic PTEN variant or in cis with multiple pathogenic variants.' The evidence for this variant shows no phase data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 (Supporting) is: 'In-frame deletions/insertions in repetitive region without functional impact.' The evidence for this variant shows it is intronic outside repetitive region. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BP4 (Supporting) is: 'Multiple lines of computational evidence suggest no impact (splicing variants require concordance of SpliceAI and VarSeak).' The evidence for this variant shows SpliceAI = 0 but no VarSeak data. Therefore, BP4 is not applied due to incomplete splicing algorithm concordance.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BP5 (Supporting) is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows no alternate molecular basis. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 (Supporting) is: 'Reputable source classifies variant as benign.' The evidence for this variant shows no such classification. Therefore, BP6 is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines for PTEN, the rule for BP7 (Supporting) is: 'A synonymous or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.' The evidence for this variant shows position +18 and SpliceAI score of zero. Therefore, BP7 is applied at Supporting strength because it is an intronic variant beyond +7 with no predicted splice impact.