PTEN c.802-1G>T, p.Splice_Site
NM_000314.8:c.802-1G>T
COSMIC ID: COSM7431685
Pathogenic
c.802-1G>T in PTEN disrupts a canonical splice site, fulfilling PVS1 at Very Strong and PM2 at Supporting strength. No additional criteria are met. The combination of PVS1 and PM2 supports a final classification of Likely Pathogenic.
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.802-1G>T
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
COSM7431685
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.802-1G>T
Active Tracks
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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
3 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
The c.802-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 8 of the PTEN gene. This alteration has been reported in the literature in a 45-year-old man with a history of an overall polyp burden of more than 100 polyps, macrocephaly and classic mucocutaneous findings including trichilemmomas and oral papillomas consistent with a diagnosis of Cowden Syndrome (Modi RM et al. Clin Gastroenterol Hepatol, 2017 08;15:e131-e132). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Donor and acceptor splice site variants 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 sequence change affects an acceptor splice site in intron 7 of the PTEN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with Cowden syndrome (PMID: 27477328, 28677221). ClinVar contains an entry for this variant (Variation ID: 827401). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28677221, 28013114]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28677221].
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 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: 8.48
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule/finding for PVS1 is: 'Very Strong Strength: Very Strong Use PTEN PVS1 decision tree.' The evidence for this variant shows: c.802-1G>T disrupts the canonical splice acceptor site (±1 position) in a gene where loss of function is a known mechanism and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant is predicted to abolish normal splicing in PTEN.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS1 is: '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 previously established pathogenic variant at this nucleotide position causing an identical outcome. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS2 is: 'Strong: 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 segregation 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 in vitro or in vivo functional assay data are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS4 is: 'Strong: Probands with specificity score 4-15.5 OR significantly increased prevalence in affected vs controls.' The evidence for this variant shows: no case count or case–control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM1 is: 'Moderate: Located in a mutational hot spot and/or critical functional domain defined to include residues in catalytic motifs: 90-94, 123-130, 166-168.' The evidence for this variant shows: this is a splice site variant, not within a defined PTEN catalytic motif. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule/finding for PM2 is: 'Supporting: Absent in population Databases present at <0.00001 allele frequency in gnomAD.' The evidence for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent in large population datasets.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: PTEN-associated disease is autosomal dominant and no trans-phase data are applicable. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM4 is: 'Moderate: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: this is a splice variant, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM5 is: 'Moderate: 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: it is a splice site change, not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM6 is: 'Moderate: Assumed de novo without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP1 is: 'Supporting: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.' The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP2 is: 'Supporting: Missense variant in a gene with a low rate of benign missense variation where missense is common mechanism.' The evidence for this variant shows: it is a splice site change, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP3 is: 'Supporting: Multiple lines of computational evidence support a deleterious effect; splicing variants require concordance of SpliceAI and VarSeak.' The evidence for this variant shows: SpliceAI predicts high impact but VarSeak data are not available. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP4 is: 'Supporting: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no detailed phenotype or clinical presentation data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: 'Reputable source reports variant as pathogenic but evidence is not available for independent evaluation.' The evidence for this variant shows: ClinVar reports exist but PP5 is no longer recommended by VCEP. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BA1 is: 'Stand Alone: 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/finding for BS1 is: 'Strong: allele frequency 0.0043%–0.056% in gnomAD.' 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/finding for BS2 is: 'Strong: Observed in homozygous state in a healthy individual.' The evidence for this variant shows: no homozygous observations in unaffected individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS3 is: 'Strong: Functional studies show no damaging effect on protein function.' The evidence for this variant shows: no functional studies demonstrating lack of effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS4 is: 'Strong: 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/finding for BP1 is: 'Supporting: Missense variant in gene where truncating variants are known mechanism.' The evidence for this variant shows: it is a splice site change, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP2 is: 'Supporting: Observed in trans with a pathogenic PTEN variant or multiple observations in cis.' The evidence for this variant shows: no cis/trans data available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: 'Supporting: In-frame indels in a repetitive region.' The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP4 is: 'Supporting: Multiple lines of computational evidence suggest no impact; splicing variants require concordance of SpliceAI and VarSeak.' The evidence for this variant shows: SpliceAI predicts high impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: 'Supporting: Variant found in case with alternative 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/finding for BP6 is: 'Supporting: Reputable source reports variant as benign but evidence is not available.' The evidence for this variant shows: no reputable benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP7 is: 'Supporting: Synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact.' The evidence for this variant shows: it is at -1 position with predicted splicing impact. Therefore, this criterion is not applied.