PTEN c.1027-2A>G, p.Splice_Site
NM_000314.8:c.1027-2A>G
COSMIC ID: COSM5966
Pathogenic
The variant c.1027-2A>G in PTEN is classified as Likely Pathogenic based on VCEP PVS1 Very Strong for canonical splice site LOF, PM2 Supporting for absence from population databases, and PP3 Supporting for strong computational splice-impact predictions.
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.1027-2A>G
Protein Change
Splice
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM5966
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.1027-2A>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
4 publications
Likely Pathogenic
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
7 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
The c.1027-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the PTEN gene. This alteration was first described in a 9-month-old male with developmental delay, and was also detected in his father, who had a clinical diagnosis of Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Varga EA et al. Genet. Med. 2009 Feb; 11(2):111-7). This alteration has also been described in a patient with synchronous bilateral breast cancer, benign trichilemmoma, oral mucosal papillomatosis, and acral keratoses (Peiró G et al. Breast J. 2010;16(1):77-81). In one laboratory analysis, this alteration was detected in 1/802 samples submitted for clinical PTEN testing (Pilarski R et al. J. Med. Genet. 2011 Aug; 48(8):505-12). Another pathogenic alteration at the same nucleotide position (c.1027-2A>C) has also been described in an individual with Cowden syndrome (Tan MH et al. Am J Hum Genet. 2011;88(1):42-56). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is also known as IVS8-2A>G in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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 a disease-causing mutation.
This sequence change affects an acceptor splice site in intron 8 of the PTEN gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease (PMID: 11052475, 19265751, 19968660, 27477328, 28526761; Invitae). This variant is also known as IVS8-2A>G. ClinVar contains an entry for this variant (Variation ID: 427581). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
This variant is considered likely 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: 19265751, 27477328, 11052475, 21659347, 19968660].
The c.1027-2A>G variant in the PTEN gene is expected to disrupt the splicing acceptor site in intron 8 (SpliceAI, delta score = 0.99), and is expected to alter RNA splicing, leading to disrupted protein structure and function. Disruption of this splice site is also known as IVS8-2A>G in the early literature. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant has been observed in individuals with PTEN hamartoma tumor syndrome (PHTS), macrocephaly, developmental delay, Cowden syndrome, and Lhermitte-Duclos disease (PMID: 11052475, 19265751, 19968660, 21659347, 27477328, 28526761, 32190315, 21659347, 21194675). Other variants affecting the same splicing locus, c.1027-2A>C, c.1027-1G>C, and c.1027-1G>A, have been reported as pathogenic in ClinVar. In addition, this variant is absent in the general population database according to gnomAD. Therefore, the c.1027-2A>G variant in the PTEN gene has been classified as pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Likely 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: 6.69
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "**Very Strong Strength**: Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: c.1027-2A>G affects the canonical splice acceptor site, predicted to abolish normal splicing and result in loss of function. Therefore, this criterion is applied at Very Strong strength because a canonical ±1/2 splice site variant in PTEN meets the VCEP PVS1 decision tree for LOF.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "**Strong Strength**: 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 known pathogenic variant at this exact position with demonstrated equivalent splice impact. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "**Strong Strength**: 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 data 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 RNA or mini-gene splicing assay data. Therefore, this criterion is not applied due to lack of functional study evidence.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "**Strong Strength**: Probands with specificity score 4-15.5 OR significant enrichment in cases vs controls." The evidence for this variant shows: no proband or case-control data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "**Moderate Strength**: Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: position c.1027-2 is outside defined hotspots/domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "**Supporting Strength**: Absent in population Databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows: not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from large control datasets.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders with trans observations. The evidence for this variant shows: no data on trans occurrences in a recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "**Moderate Strength**: Protein length changes due to in-frame indels in non-repeat regions or stop-loss variants." The evidence for this variant shows: it is a splice-site variant, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "**Moderate Strength**: Missense change at an amino acid residue where a different pathogenic missense change has been seen." The evidence for this variant shows: variant affects splicing, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "**Moderate Strength**: Assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "**Supporting Strength**: Co-segregation with disease in multiple affected family members (3-4 meioses)." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense rate. The evidence for this variant shows: it is a splice-site variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "**Supporting Strength**: 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 high impact on splicing (score 0.99). Therefore, this criterion is applied at Supporting strength because computational tools concordantly predict splice disruption.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies when the patient’s phenotype is highly specific for a disorder with a 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, PP5 applies when a reputable source reports a variant as pathogenic without available evidence. The VCEP does not recommend PP5 use. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "**Stand Alone Strength**: 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: "**Strong Strength**: allele frequency from 0.000043 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: "**Strong Strength**: Observed in homozygous state in healthy individuals." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "**Strong Strength**: Well-established functional studies show no damaging effect." The evidence for this variant shows: no functional data demonstrating lack of impact. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "**Strong Strength**: Lack of segregation in ≥2 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, BP1 applies to missense variants in a gene where truncating variants are the only mechanism of disease. The evidence for this variant shows: it is a splice-site variant, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "**Supporting Strength**: Observed in trans with a pathogenic PTEN variant or ≥3 observations in cis." The evidence for this variant shows: no phase data with other PTEN variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: it is a splice-site SNV. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "**Supporting Strength**: Multiple lines of computational evidence suggest no impact." 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, BP5 applies when a variant is 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, BP6 applies when a reputable source reports a variant as benign without available evidence. The VCEP does not recommend BP6 use. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "**Supporting Strength**: A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact." The evidence for this variant shows: it is at −2, within the splice consensus. Therefore, this criterion is not applied.