PTEN c.1027-1G>C, p.Splice_Site
NM_000314.8:c.1027-1G>C
COSMIC ID: COSM1180410
Pathogenic
This canonical splice acceptor variant c.1027-1G>C in PTEN disrupts the −1 splice site, is absent from population databases, and is predicted deleterious by computational tools. PVS1_Very Strong plus three Supporting criteria (PM2, PP3, PP5) support a Likely 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.1027-1G>C
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
COSM1180410
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.1027-1G>C
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
Likely Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 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: 6.93
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Null Variants in a gene where LOF is known mechanism of disease". The evidence for this variant shows: c.1027-1G>C disrupts the canonical splice acceptor site at position -1, predicted to abolish normal splicing and result in loss of function. Therefore, this criterion is applied at Very Strong strength because this is a canonical ±1 position splice site variant in PTEN, a gene where loss of function is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "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 splicing variant at nucleotide c.1027-1 in PTEN reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 (Strong) is: "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, parental testing not reported. 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 splicing assay data available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Probands with specificity score ≥16 or significant increased prevalence in cases versus controls". The evidence for this variant shows: no case-control or proband frequency data reported. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "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: the variant affects a splice site, not within a defined hot spot or functional motif. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD". The evidence for this variant shows: not present in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population cohorts.
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: PTEN-related disease is autosomal dominant and trans data are not relevant or not provided. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants". The evidence for this variant shows: this is a splice site variant, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "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: this is a splice site variant, 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: "Assumed de novo, without confirmation of paternity/maternity" or higher thresholds. The evidence for this variant shows: no de novo assumptions or parental testing data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense is common mechanism". The evidence for this variant shows: not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 for splicing variants is: "Multiple lines of computational evidence support a deleterious effect (SpliceAl and VarSeak concordance)". The evidence for this variant shows: SpliceAI score of 0.99 indicating high impact on splicing. Therefore, this criterion is applied at Supporting strength because in silico tools predict a significant splicing impact.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with single genetic etiology". The evidence for this variant shows: no detailed phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic but evidence not available". The evidence for this variant shows: reported in ClinVar as Pathogenic (1 lab) and Likely Pathogenic (1 lab). Therefore, this criterion is applied at Supporting strength because a reputable database supports a pathogenic assertion without publicly available evidence.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "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: "gnomAD Filtering allele frequency from 0.0043% up to 0.056%". 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: "Observed in homozygous state in healthy individuals". The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Functional studies show no damaging effect". 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: "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 for BP1 is: "Missense variant in gene with only truncating variants known to cause disease". The evidence for this variant shows: 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: "Observed in trans with a pathogenic PTEN variant" or multiple cis observations. The evidence for this variant shows: no phase information or multiple cis observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive region without functional impact". 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 for BP4 is: "Multiple lines of computational evidence suggest no impact (SpliceAl and VarSeak concordance)". The evidence for this variant shows: computational predictions indicate a deleterious splicing effect (SpliceAI 0.99). Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no alternate genetic etiology reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without evidence". The evidence for this variant shows: no reputable benign assertions. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant at or beyond +7/-21 with no splicing impact". The evidence for this variant shows: affects canonical splice site at -1. Therefore, this criterion is not applied.