PTEN c.1027-1G>A, p.Splice_Site
NM_000314.4:c.1027-1G>A
COSM5962
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Likely Pathogenic
2 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
18 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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_000314.4:c.1027-1G>A
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
COSM5962
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
2 publications
Likely Pathogenic
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
2 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratories) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen expert panel.
Expert Panel Reviews
Pathogenic
Clingen PTEN Variant Curation Expert Panel, Clingen
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
Functional Studies
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 6.96
VCEP Guidelines
Applied ACMG/AMP Criteria
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 is a canonical splice site alteration at the −1 position, predicted to result in loss of function in PTEN, a gene where LOF 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 null variants at canonical splice sites.
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 splice variant at the exact nucleotide with demonstrated equivalent impact. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 (Strong strength) 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 occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN pre-processing results, 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 splicing assay data are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 (Strong strength) is: "Strong: Probands with specificity score 4–15.5 OR significant enrichment in cases vs. controls." The evidence for this variant shows: no case-level or case-control data with specificity scores. 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: splice acceptor site falls outside defined catalytic motifs. 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 or another large sequenced population." The evidence for this variant shows: not found in gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because it is absent from large population databases.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no trans-phase data 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 deletions/insertions or stop-loss variants in non-repeat regions." The evidence for this variant shows: it is an intronic splice site change, 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 missense change is pathogenic." The evidence for this variant shows: it is a splice site alteration, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM6 (Strong strength) is: "Strong: Two probands with presumed de novo occurrence without confirmation." The evidence for this variant shows: no presumed de novo observations reported. 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 familial segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: Missense variant in a gene with low rate of benign missense variation where missense variants are common mechanism of disease." 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 SpliceAl and VarSeak." The evidence for this variant shows: SpliceAI predicts a high impact on splicing (score 0.99). Therefore, this criterion is applied at Supporting strength because computational tools predict disruption of splicing.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no clinical phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Reputable source reports variant as pathogenic but evidence not available to the laboratory." The evidence for this variant shows: ClinVar entries from three clinical laboratories and the ClinGen PTEN Expert Panel classify it as Pathogenic/Likely Pathogenic. Therefore, this criterion is applied at Supporting strength because multiple reputable sources report it as pathogenic without primary evidence available.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: gnomAD Filtering allele frequency from 0.000043 to 0.00056." The evidence for this variant shows: allele frequency is 0% in gnomAD. 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 the homozygous state in a healthy or PHTS-unaffected 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 for BS3 is: "Strong Strength: Well-established in vitro or in vivo functional studies show no damaging effect on protein function (including splicing assays)." 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 for BS4 is: "Strong Strength: Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data demonstrating lack of cosegregation. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Missense variant in a gene where truncating variants are known mechanism of disease." The evidence for this variant shows: it is a splice site variant. 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 or likely pathogenic PTEN variant or ≥3 observations in cis with different pathogenic variants." The evidence for this variant shows: no cis/trans observations with other PTEN variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame indels in a repetitive region without known function." The evidence for this variant shows: it is a splice site variant, 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 Strength: Multiple lines of computational evidence suggest no impact on gene or gene product (e.g., concordant benign predictions)." The evidence for this variant shows: computational predictions are discordant with strong SpliceAI indication of impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: Reputable source reports variant as benign but no evidence available." The evidence for this variant shows: no reputable source reporting this variant as benign. 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 −1 position, within the canonical splice site. Therefore, this criterion is not applied.