PTEN c.635-1G>A, p.Splice_Site
NM_000314.8:c.635-1G>A
COSMIC ID: COSM28920
Pathogenic
This canonical splice acceptor variant in PTEN is absent from controls, predicted to disrupt normal splicing leading to loss of function, and is classified as Likely Pathogenic based on PVS1 (Very Strong), PM2 (Supporting), PP3 (Supporting), and PP5 (Supporting).
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.635-1G>A
Protein Change
Splice
Location
Exon 6
(Exon 6 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM28920
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.635-1G>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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
2 publications
Likely Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
3 Path
2 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
This sequence change affects an acceptor splice site in intron 6 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 individual(s) with PTEN-related conditions (PMID: 19265751, 21659347, 24379037). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 427598). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
The c.635-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 7 of the PTEN gene. This variant was identified in 1 of 802 individuals with features of Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome undergoing PTEN analysis (Pilarski R et al. J Med Genet, 2011 Aug;48:505-12). This variant was reported in an individual who met clinical criteria for PTEN hamartoma tumor syndrome (Varga EA et al. Genet Med, 2009 Feb;11:111-7; Hansen-Kiss E et al. J Med Genet, 2017 Jul;54:471-478). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 may result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, 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 likely pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (2 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: 7.42
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines for PTEN: "Very Strong Strength: Use PTEN PVS1 decision tree." The variant NM_000314.8:c.635-1G>A is a canonical splice acceptor change predicted to result in loss of function in PTEN, where loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for an essential splice site variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Different variant at same nucleotide position as a pathogenic splicing variant..." There is no previously established pathogenic splicing variant at this exact nucleotide position. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: de novo occurrence requires confirmed maternity and paternity. No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN pre-processing: variant not found in PTEN functional data file, and no in vitro or in vivo functional studies (e.g., splicing assays) are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: case-level or case-control data (specificity score) required. No case reports or case-control frequency data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: location in critical functional domain (residues 90-94, 123-130, 166-168). This is a splice site variant, not a missense in those motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "Supporting: Absent in population databases present at <0.00001 allele frequency in gnomAD." The variant is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the allele frequency is below the threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM3 requires observation in trans with a pathogenic variant in a recessive gene. No trans-phase data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: in-frame insertions/deletions or stop-loss variants required. This is a splice site variant. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: missense change at a residue with a different known pathogenic missense. This is a splice variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: presumed de novo without confirmation. No such data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: segregation data across multiple affected family members required. No segregation information is available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: missense variant in gene with low benign missense rate. This is a splice variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines: "Supporting: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak." SpliceAI predicts an acceptor loss with a score of 0.98, indicating high impact on splicing. Therefore, this criterion is applied at Supporting strength because computational tools concordantly predict deleterious impact.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: specific phenotype with single genetic etiology required. No detailed phenotype or family history matching PTEN-related syndromes provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: "Supporting: Reputable source recently reports variant as pathogenic, but evidence not available for independent evaluation." ClinVar reports this variant as Pathogenic by three laboratories and Likely Pathogenic by two. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: filtering allele frequency >0.00056 required. The variant is absent. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: allele frequency 0.000043–0.00056 required. The variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: observed homozygous in unaffected individual required. No such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: well-established functional studies show no damaging effect. No functional studies demonstrate no impact. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: lack of segregation evidence in affected members of ≥2 families required. No segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: missense in gene where only truncating variants are pathogenic. This is a splice variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: observed in trans or in cis with other pathogenic variant required. No such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: in-frame indel in repetitive region. This is a splice site. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: computational evidence suggests no impact. Here, computational evidence predicts high impact on splicing. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: variant found in case with alternate molecular basis. No evidence of alternate etiology. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: reputable source reports benign. No such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: synonymous or intronic variant beyond +7/-21 with no splicing impact. This is a -1 splice site. Therefore, this criterion is not applied.