PTEN c.210-14A>G, p.?
NM_000314.8:c.210-14A>G
Variant of Uncertain Significance (VUS)
This intronic variant at c.210-14 in PTEN is absent from population databases (PM2_Supporting) and computational predictors (SpliceAI) suggest a splicing impact (PP3_Supporting). However, in the absence of functional, segregation, or clinical evidence, it remains a Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM2
PP3
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.210-14A>G
Protein Change
?
Location
Exon 3
(Exon 3 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.210-14A>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 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
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).
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: 1.85
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific'. The evidence for this variant shows an intronic alteration at c.210-14, outside the canonical splice donor/acceptor sites (±1/±2). Therefore, PVS1 is not applied because PTEN PVS1 requires disruption of the canonical splice sites for null effect.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS1 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 no amino acid change or established analogous pathogenic variant. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS2 Strong: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.' There is no de novo or parental testing information available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS3 Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. RNA, mini-gene, or other assay shows impact on splicing.' PTEN pre-processing did not identify this variant in functional assay datasets. Therefore, PS3 is not applied due to lack of functional study data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: PS4 relates to increased prevalence in affected individuals or proband specificity scores. There are no case or cohort data for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM1 Moderate: Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168).' This variant is intronic and not within a defined PTEN functional domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: 'PM2 Supporting: Absent in population databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.' The evidence for this variant shows MAF=0% in gnomAD. Therefore, PM2 is applied at Supporting strength because the variant is absent from population databases as specified.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: PM3 addresses recessive inheritance with in trans observations. There is no evidence of this variant observed in trans with a pathogenic PTEN variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM4 Moderate: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' This variant does not alter protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM5 Moderate: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' This variant is intronic and not a missense change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: PM6 addresses presumed de novo observations without confirmation. There is no de novo information for this variant. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: PP1 addresses co-segregation in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG: 'PP2 Supporting: Missense variant in a gene that has a low rate of benign missense variation where missense is a common mechanism.' This variant is intronic. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines: 'PP3 Supporting: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak.' The evidence for this variant shows SpliceAI maximum score of 0.85 predicting acceptor gain. Therefore, PP3 is applied at Supporting strength due to predicted splicing alteration.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG: 'PP4 Supporting: Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.' No phenotype data were provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG: 'PP5 Supporting: Reputable source recently reports variant as pathogenic without available evidence.' The only ClinVar entry is Uncertain significance. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BA1 Stand Alone: gnomAD Filtering allele frequency >0.00056 (0.056%).' The variant frequency is 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS1 Strong: gnomAD Filtering allele frequency from 0.000043 up to 0.00056.' The variant frequency is 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS2 Strong: Observed in homozygous state in healthy individual.' No homozygous observations are reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS3 Strong: Functional studies show no damaging effect on protein function.' No functional studies demonstrating lack of impact are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS4 Strong: Lack of segregation in affected members of two or more families.' No segregation data exist. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG: 'BP1 Supporting: Missense variant in gene where only truncating variants cause disease.' This variant is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP2 Supporting: Observed in trans with a pathogenic PTEN variant.' No such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP3 Supporting: In-frame indels in repetitive region.' This variant is not an in-frame indel. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP4 Supporting: Computational evidence suggests no impact.' In silico predictions are mixed and SpliceAI predicts impact. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP5 Supporting: Variant found in a case with an alternate molecular basis.' No alternate molecular basis is documented. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG: 'BP6 Supporting: Reputable source reports variant as benign without evidence.' No such benign report exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP7 Supporting: A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact.' Although this variant is at -14 (beyond -7), SpliceAI predicts a significant splicing impact. Therefore, BP7 is not applied.