PTEN c.635-1G>C, p.Splice_Site
NM_000314.8:c.635-1G>C
COSM921121
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Likely Pathogenic
3 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
5 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_000314.8:c.635-1G>C
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
COSM921121
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 251436
Alt: 0
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0%, 0/251436 alleles, homozygotes = 0) but does not appear at a higher frequency in any of the selected populations. The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Likely Pathogenic
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
3 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (2 clinical laboratories).
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: 7.31
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease.' The evidence for this variant shows it is a canonical splice acceptor change at c.635-1G>C, disrupting normal splicing in PTEN. Therefore, this criterion is applied at Very Strong strength because it abolishes the canonical splice site in a LOF‐sensitive gene.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS1 is: '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 prior pathogenic variant at this exact nucleotide position producing the same consequence. Therefore, PS1 is not applied because there is no established pathogenic change at this site.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 (Very Strong) is: 'Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.' The evidence for this variant shows no de novo occurrence data. Therefore, PS2 is not applied due to lack of de novo confirmation.
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 confirms no in vitro or in vivo functional assays reporting impact. Therefore, PS3 is not applied because there are no functional data demonstrating a damaging or benign effect.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 (Very Strong) is: 'Probands with specificity score ≥16.' The evidence for this variant shows no case‐level data or specificity scoring. Therefore, PS4 is not applied due to absence of case series or statistical enrichment data.
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. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3).' The evidence for this variant shows it affects a splice site outside of defined catalytic motifs. Therefore, PM1 is not applied because it is not within a recognized functional domain or hotspot.
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 or another large sequenced population.' The evidence for this variant shows a gnomAD allele frequency of 0% (0/251436 alleles). Therefore, PM2 is applied at Supporting strength because the variant is absent from large population datasets.
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 it is observed heterozygously with no second allele data. Therefore, PM3 is not applied because there is no evidence of trans configuration with another pathogenic PTEN variant.
PM4
PM4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows it is a splice site change, not an in-frame indel or stop-loss. Therefore, PM4 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 or likely pathogenic has been seen before.' The evidence for this variant shows it is a splice site change, not a missense variant. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM6 (Very Strong) is: 'Two proven OR four assumed OR one proven + two assumed de novo observations.' The evidence for this variant shows no de novo data without confirmation. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP1 (Supporting) is: 'Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.' The evidence for this variant shows no segregation data. Therefore, PP1 is not applied due to lack of family studies.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows it is a splice variant, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: '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 acceptor loss with a score of 0.98 and other in silico predictors support splicing disruption. Therefore, PP3 is applied at Supporting strength because strong computational data predict altered splicing.
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 a single genetic etiology.' The evidence for this variant shows no detailed phenotype data. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows multiple ClinVar submissions (4 Pathogenic, 2 Likely Pathogenic). Therefore, PP5 is applied at Supporting strength because of reputable clinical reports.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'gnomAD Filtering allele frequency >0.00056 (0.056%).' The evidence for this variant shows allele frequency of 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).' The evidence for this variant shows allele frequency of 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Observed in the homozygous state in a healthy or PHTS-unaffected individual.' The evidence for this variant shows no homozygotes in healthy cohorts. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.' The evidence for this variant shows no functional studies demonstrating lack of effect. Therefore, BS3 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 studies. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where LOF is a known mechanism of disease.' The evidence for this variant shows it is a splice variant causing LOF. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown.' The evidence for this variant shows no cis/trans data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP3 is: 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.' The evidence for this variant shows it is at the -1 position. Therefore, BP3 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 on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak.' The evidence for this variant shows high-impact splicing predictions. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP 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 diagnoses. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows no benign ClinVar reports. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.' The evidence for this variant shows it is at -1. Therefore, BP7 is not applied.