PTEN c.253+2T>A, p.Splice_Site
NM_000314.8:c.253+2T>A
COSMIC ID: COSM9274197
Pathogenic
This intronic +2 splice site variant in PTEN is absent from population databases, computationally predicted to disrupt splicing, and reported as pathogenic in ClinVar. Applying PVS1_Very Strong, PM2_Supporting, PP3_Supporting, and PP5_Supporting yields a Pathogenic classification.
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.253+2T>A
Protein Change
Splice
Location
Exon 4
(Exon 4 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM9274197
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.253+2T>A
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 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Studies have shown that disruption of this splice site results in partial intron inclusion and introduces a premature termination codon (PMID: 11071384). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 468676). Disruption of this splice site has been observed in individual(s) with juvenile polyposis syndrome and breast cancer and Cowden disease (PMID: 9259288, 17873119, 26681312). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the PTEN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
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: 7.43
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. Modification Type: Disease-specific". The evidence for this variant shows it affects the canonical +2 splice donor site in PTEN, a gene where loss of function is a known mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null splice site variant in PTEN as per the decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule 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 known pathogenic variant at the same nucleotide or resulting in the same amino acid/splicing outcome. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PS2 is: "Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." There are no de novo data available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing: the variant was not found in PTEN-specific functional study datasets indicating no functional characterization. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PS4 is: "Strong Probands with specificity score 4-15.5 OR prevalence significantly increased in affected vs controls." There are no case or proband count data for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM1 is: "Moderate Located in a mutational hot spot and/or critical functional domain (residues 90-94,123-130,166-168)." This variant is a splice site variant not located within those defined domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: the rule 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. Therefore, this criterion is applied at Supporting strength because it is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG: the rule for PM3 is for recessive disorders when variant is observed in trans with a pathogenic variant. This is not applicable for PTEN (dominant) and no trans observations exist. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM4 is: "Moderate Protein length changes due to in-frame indels or stop-loss variants." This is a splice site variant. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM5 is: "Moderate Missense change at a residue where a different pathogenic missense change exists." This is not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM6 is: "Very Strong or Strong assumed de novo observations without confirmation." There are no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PP1 is: "Supporting co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG: the rule for PP2 is: "Supporting missense variant in gene with low benign missense variation." This is not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines: the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect. Splicing variants: Concordance of SpliceAI and VarSeak." The evidence shows SpliceAI predicts a high-impact donor loss (score 0.99). Therefore, this criterion is applied at Supporting strength because computational tools indicate a deleterious splicing effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG: the rule for PP4 is: "Supporting phenotype highly specific for a single genetic etiology." No detailed phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG: the rule for PP5 is: "Supporting Reputable source reports variant as pathogenic but evidence is not available." The evidence shows ClinVar reports this variant as Pathogenic from three clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BA1 is: "Stand Alone allele frequency >0.00056 in gnomAD." This variant is not present in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS1 is: "Strong allele frequency from 0.000043 up to 0.00056 in gnomAD." This variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS2 is: "Strong observed homozygous in healthy individual." There are 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 functional studies show no damaging effect." No such studies exist. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS4 is: "Strong lack of segregation in multiple families." No segregation data exist. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG: the rule for BP1 is: "Supporting missense in a gene where truncating variants are common mechanism." This is not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BP2 is: "Supporting observed in trans with a pathogenic PTEN variant." No such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG: the rule for BP3 is: "Supporting in-frame indels in repetitive regions." This is not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BP4 is: "Supporting computational evidence suggests no impact." Computational evidence indicates a high-impact splice disruption. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG: the rule for BP5 is: "Supporting variant found in a case with an alternate molecular basis." No data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG: the rule for BP6 is: "Supporting reputable source reports variant as benign." No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BP7 is: "Supporting synonymous or intronic variant at or beyond +7/-21 with no splicing impact." This variant is at +2 and is predicted to affect splicing. Therefore, this criterion is not applied.