PTEN c.210-1G>T, p.Splice_Site
NM_000314.8:c.210-1G>T
COSMIC ID: COSM5965
Pathogenic
c.210-1G>T affects the canonical splice acceptor site of PTEN, meeting PVS1 (Very Strong) and PM2 (Supporting) but lacking additional supporting criteria, resulting in an overall classification of Uncertain significance.
ACMG/AMP Criteria Applied
PVS1
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.210-1G>T
Protein Change
Splice
Location
Exon 3
(Exon 3 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM5965
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.210-1G>T
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
Likely Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar 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: 7.09
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Null Variant (nonsense, fs, start codon, splicing +1/2 ...) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows: c.210-1G>T affects the canonical splice acceptor site predicted to abolish normal splicing, resulting in loss of function of PTEN. Therefore, this criterion is applied at Very Strong strength because it is a canonical splice site variant in a LOF‐sensitive gene.
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 OR different variant at same nucleotide position as a pathogenic splicing variant...". The evidence for this variant shows: no known pathogenic splicing variant reported at this exact nucleotide. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history". The evidence for this variant shows: no de novo inheritance data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "The variant has not been functionally characterized." The evidence for this variant shows: no RNA, mini-gene, or in vitro functional studies available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Increased prevalence of variant in affected individuals compared with controls or probands specificity score ≥4". The evidence for this variant shows: no case series, no specificity scores reported. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 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: position c.210-1 is outside of the defined catalytic motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Absent in population Databases present at <0.00001 allele frequency in gnomAD". The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
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". The evidence for this variant shows: PTEN is autosomal dominant and no trans data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in‐frame indels or stop‐loss variants". 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: "Missense change at a residue where a different missense change is known pathogenic". The evidence for this variant shows: it is a splice variant, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity/maternity". The evidence for this variant shows: no de novo inheritance information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Co‐segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data reported. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism". The evidence for this variant shows: it is a splice site variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect – for splicing variants: concordance of SpliceAI and VarSeak". The evidence for this variant shows: only SpliceAI predicts impact; VarSeak data unavailable. Therefore, this criterion is not applied due to lack of concordant in silico tools.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype is highly specific for a disease with single genetic etiology". The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic but evidence not available". The evidence for this variant shows: ClinVar entry exists but evidence not accessible; however, ClinGen discourages PP5. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "gnomAD filtering allele frequency >0.00056". The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Allele frequency 0.000043–0.00056 in gnomAD". 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: "Observed homozygous in healthy individual". 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: "Well‐established functional studies show no damaging effect". The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected members". 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: "Missense variant in a gene where only truncating variants cause disease". The evidence for this variant shows: it is a splice variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant". The evidence for this variant shows: no evidence of cis/trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive region". The evidence for this variant shows: splice site variant, not in repeat. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: conflicting predictions. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Variant found in case with alternative molecular basis". The evidence for this variant shows: no alternate diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence not available". The evidence for this variant shows: no benign classifications. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant at or beyond +7/-21 with no splicing impact". The evidence for this variant shows: position at -1, within the splice consensus. Therefore, this criterion is not applied.