PTEN c.634+1del, p.Splice_Site
NM_000314.8:c.634+1del
Variant of Uncertain Significance (VUS)
This canonical +1 splice site deletion in PTEN disrupts normal splicing and leads to loss of function. It is absent in population databases (PM2 Supporting) and computational tools predict splicing disruption (PP3 Supporting). PVS1 is applied at Very Strong per PTEN VCEP decision tree. Combined evidence supports classification as Likely Pathogenic.
ACMG/AMP Criteria Applied
PVS1
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.634+1del
Protein Change
Splice
Location
Exon 6
(Exon 6 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.634+1del
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
Unknown
PP3 Applied
No
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, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease'. The evidence for this variant shows: c.634+1del disrupts the canonical +1 splice donor site of PTEN, a gene with established loss-of-function disease mechanism. Therefore, this criterion is applied at Very Strong strength because disruption of the +1 splice site meets the VCEP PVS1 decision tree for PTEN.
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, where in silico models predict impact equal to or greater than the known pathogenic variant'. The evidence for this variant shows: no previously established pathogenic variant at this position. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: 'Functional studies (PS3): The variant has not been functionally characterized.' The evidence for this variant shows: no functional assay data exist. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls or probands with specificity score ≥4'. The evidence for this variant shows: no case or prevalence data available. 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 (PTEN catalytic motifs 90-94, 123-130, 166-168)'. The evidence for this variant shows: c.634+1 is outside defined PTEN 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 or another large sequenced population'. The evidence for this variant shows: not found in gnomAD or other large population databases. Therefore, this criterion is applied at Supporting strength because the allele is absent from controls.
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-related disorders are dominant and no trans data exist. 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 deletions/insertions'. The evidence for this variant shows: this is a splice donor site deletion, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before'. The evidence for this variant shows: this is not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo data at all. 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. 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 where missense is a common mechanism'. The evidence for this variant shows: this is a splice variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: '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 predicts a high likelihood of donor loss (score 0.99). Therefore, this criterion is applied at Supporting strength because computational tools concordantly predict disruption of splicing.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history 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 reports variant as pathogenic'. The evidence for this variant shows: not reported in ClinVar or other databases. 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 is 0. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'gnomAD Filtering allele frequency from 0.000043 up to 0.00056'. The evidence for this variant shows: allele frequency is 0. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Observed in the homozygous state in a healthy individual'. The evidence for this variant shows: no such 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 available. 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 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: 'Missense variant in a gene for which only truncating variants are known to cause disease'. The evidence for this variant shows: this 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 trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region'. The evidence for this variant shows: not an in-frame change in a repeat region. 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: computational evidence predicts a damaging effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no alternate molecular basis reported. 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'. The evidence for this variant shows: not reported. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'A synonymous or intronic variant at or beyond +7/-21 with no predicted impact'. The evidence for this variant shows: variant affects +1 splice site. Therefore, this criterion is not applied.