PTEN c.*8T>G, p.?
NM_000314.8:c.*8T>G
Variant of Uncertain Significance (VUS)
The variant NM_000314.8:c.*8T>G in PTEN lies in the 3′ UTR with no coding impact. It is absent from population databases (PM2_supporting) and computational tools predict no effect (BP4_supporting). No functional, segregation, de novo or phenotype data are available. Therefore, it remains a Variant of Uncertain Significance.
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.*8T>G
Protein Change
?
Location
Exon 9
(Exon 9 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.*8T>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
Uncertain Significance (VUS)
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Benign (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
Functional Summary
The PTEN *8t>G variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.04
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PVS1 rule is: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows it is NM_000314.8:c.*8T>G located in the 3′ UTR, not predicted to truncate or abolish the protein. Therefore, this criterion is not applied because the variant does not create a null allele.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PS1 rule is: "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...". The evidence for this variant shows no amino acid change (3′ UTR). Therefore, this criterion is not applied because there is no amino acid alteration.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the PS2 rule is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". There are no reports of de novo occurrence. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing findings, functional studies for this variant have not been characterized ("The PTEN *8T>G variant has not been functionally characterized"). Therefore, PS3 is not applied due to absence of functional assay data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the PS4 rule is: "The prevalence of the variant in affected individuals is significantly increased compared with controls or specificity score ≥4". No case/control or proband data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the PM1 rule is: "Located in a mutational hot spot and/or critical functional domain (residues 90–94, 123–130, 166–168)". The variant is in the 3′ UTR and not within any catalytic motif. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the PM2 rule is: "Absent in population databases present at <0.00001 allele frequency in gnomAD". The evidence shows the variant is not found in gnomAD or other large population databases. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG, the PM3 rule applies to recessive cases with observed in trans pathogenic variants. This variant is in a dominant LOF gene and there is no evidence of compound heterozygosity. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the PM4 rule is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants in functional regions". This is a single-nucleotide change in the 3′ UTR. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the PM5 rule is: "Missense change at a residue where a different missense change is pathogenic". This variant does not alter an amino acid. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the PM6 rule is: "Assumed de novo occurrence without confirmation". No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the PP1 rule is: "Co-segregation with disease in multiple affected family members". No segregation data are reported. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG, the PP2 rule is: "Missense variant in a gene with low rate of benign missense variation where missense is common mechanism". This variant is noncoding. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the PP3 rule is: "Multiple lines of computational evidence support a deleterious effect". In silico tools (CADD 2.04, SpliceAI = 0) predict no impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG, the PP4 rule is: "Patient’s phenotype is highly specific for a single gene disorder". No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG, the PP5 rule is: "Reputable source without evidence reports variant as pathogenic". ClinVar entries are conflicting (VUS and benign). Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the BA1 rule is: "gnomAD allele frequency >0.00056". The variant is absent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the BS1 rule is: "gnomAD allele frequency 0.000043–0.00056". The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the BS2 rule is: "Observed as homozygous in healthy individuals". No such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the BS3 rule is: "Well-established functional studies show no damaging effect". No splicing or functional assays have been performed. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the BS4 rule is: "Lack of segregation in affected members of ≥2 families". No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG, the BP1 rule is: "Missense in a gene where only truncating variants cause disease". This is noncoding. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the BP2 rule is: "Observed in trans with a pathogenic PTEN variant". No such observations exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG, the BP3 rule is: "In-frame indels in a repetitive region". This is a SNV in the 3′ UTR. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the BP4 rule is: "Multiple lines of computational evidence suggest no impact on gene or gene product". In silico tools (SpliceAI = 0, CADD = 2.04) predict benign. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the BP5 rule is: "Variant found in a case with an alternate molecular basis for disease". No such case data exist. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG, the BP6 rule is: "Reputable source without evidence reports variant as benign". ClinVar entries are conflicting. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the BP7 rule is: "A synonymous or intronic variant at or beyond +7/-21 with no splicing impact". This is a 3′ UTR variant. Therefore, BP7 is not applied.