PTEN c.801+1G>C, p.Splice_Site
NM_000314.8:c.801+1G>C
COSMIC ID: COSM9869414
Pathogenic
This canonical +1 splice donor variant in PTEN abolishes normal splicing, meeting VCEP PVS1 Very Strong. It is absent from population databases (PM2 supporting), predicted deleterious by splicing algorithms (PP3 supporting), and listed as pathogenic in ClinVar (PP5 supporting). The combination of PVS1 plus three supporting criteria justifies a final classification of Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PM2
PP3
PP5
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.801+1G>C
Protein Change
Splice
Location
Exon 7
(Exon 7 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM9869414
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.801+1G>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
1 publications
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change affects a donor splice site in intron 7 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Cowden syndrome (PMID: 9600246, 10234502, 11238682). ClinVar contains an entry for this variant (Variation ID: 933785). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9600246, 11071384). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as 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: 6.35
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 at Very Strong strength is: 'Null Variant (splicing +1/2) in a gene where loss of function is a known mechanism of disease; Use PTEN PVS1 decision tree'. The evidence shows this variant affects the canonical +1 splice donor site predicted to abolish normal splicing in PTEN. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for canonical splice site variants in a loss-of-function gene.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 at Strong strength 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 shows no previously reported pathogenic variant at the same nucleotide position. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 at Strong strength is: 'De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history'. The evidence shows no de novo data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN pre-processing, PS3 functional evidence: 'The variant has not been functionally characterized'. Therefore, PS3 is not applied at any strength due to absence of functional assay data.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 at Strong strength is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls'. The evidence shows no case-control or phenotype specificity data. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 at Moderate strength is: 'Located in a mutational hotspot and/or critical and well-established functional domain, including residues in catalytic motifs 90-94, 123-130, 166-168'. The evidence shows the variant affects the splice site at position +1 outside these motifs. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 at Supporting strength is: 'Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD'. The evidence shows this variant is not present in gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 at Moderate strength is: 'For recessive disorders, detected in trans with a pathogenic variant'. PTEN is an autosomal dominant gene, so PM3 is not applicable and not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 at Moderate strength is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants'. The evidence shows a splice site variant, not an in-frame indel. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 at Moderate strength is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before'. The evidence is a splice variant, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 at Moderate strength is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence shows no de novo assumptions. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 at Supporting strength is: 'Co-segregation with disease in multiple affected family members, with 3–4 meioses observed'. No segregation data provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 at Supporting strength is: 'Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The variant is a splice site change. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 at Supporting strength is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product (SpliceAI and VarSeak concordance)'. The evidence shows SpliceAI predicts donor loss with a maximum score of 1.0. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 at Supporting strength is: 'Patient’s phenotype is highly specific for a disease with a single genetic etiology'. No phenotype information provided. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 at Supporting strength is: 'Reputable source reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation'. ClinVar lists this variant as Pathogenic from one clinical laboratory. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 at Stand Alone strength is: 'gnomAD Filtering allele frequency >0.00056'. The variant has 0% frequency in gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 at Strong strength is: 'gnomAD Filtering allele frequency from 0.000043 up to 0.00056'. The variant has 0% frequency in gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 at Strong strength is: 'Observed in the homozygous state in a healthy or PHTS-unaffected individual'. No homozygous observations reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 at Strong strength is: 'Well-established in vitro or in vivo functional studies show no damaging effect'. No functional studies demonstrating lack of effect are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 at Strong strength is: 'Lack of segregation in affected members of two or more families'. No segregation data provided. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 at Supporting strength is: 'Missense variant in a gene where only loss of function causes disease'. The variant is a splice site change. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 at Supporting strength is: 'Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants'. No trans/cis data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 at Supporting strength is: 'In-frame insertions/deletions in a repetitive region without predicted impact'. The variant is a splice site change, not an in-frame indel. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 at Supporting strength is: 'Multiple lines of computational evidence suggest no impact'. The evidence shows SpliceAI predicts a high‐impact splice donor loss. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 at Supporting strength is: 'Variant found in a case with an alternate molecular basis for disease'. No alternate molecular basis is reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 at Supporting strength is: 'Reputable source reports variant as benign but the evidence is not available'. No reputable source reports this variant as benign. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 at Supporting strength is: 'A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact'. This variant is at +1. Therefore, BP7 is not applied.