PTEN c.634+1G>C, p.Splice_Site
NM_000314.8:c.634+1G>C
COSMIC ID: COSM1968250
Pathogenic
This legacy system is being phased out as Project HERA V3 is rolled out.
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.634+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
COSM1968250
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.634+1G>C
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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
3 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
The c.634+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 6 of the PTEN gene. This alteration has been reported in multiple individuals diagnosed with PTEN hamartoma tumor syndrome (PHTS) (Busch RM et al. Genet. Med. 2013 Jul;15:548-53; Chen HJ et al. Hum Mutat. 2017 10;38:1372-1377). RNA studies indicated that this alteration leads to exon 6 skipping and results in an NMD-prone transcript (Chen HJ et al. Hum Mutat. 2017 10;38:1372-1377). Another alteration impacting the same donor site (c.634+2T>C) has been shown to have a similar impact on splicing in an individual with clinical features consistent with PHTS and an individual meeting clinical criteria for PHTS (Ambry internal data; Chen HJ et al. Hum Mutat, 2017 10;38:1372-1377). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 a donor splice site in intron 6 of the PTEN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with PTEN-related conditions (PMID: 23470840, 28677221). ClinVar contains an entry for this variant (Variation ID: 427620). Studies have shown that disruption of this splice site results in skipping of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 28677221). 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: 6.72
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: it is a +1 canonical splice donor site variant predicted to result in loss of function in PTEN, where LOF is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant meets the PTEN PVS1 decision tree for a canonical splice site.
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: there is no previously established pathogenic variant at this exact nucleotide position. 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.' The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Strong: RNA, mini-gene, or other assay shows impact on splicing.' The evidence for this variant shows: no functional splicing studies or assays have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Very Strong: Probands with specificity score ≥16; Strong: probands with score 4–15.5; Moderate: score 2–3.5; Supporting: score 1–1.5.' The evidence for this variant shows: no case or prevalence data available. 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 or critical functional domain (residues 90–94, 123–130, 166–168).' The evidence for this variant shows: it alters a splice site and is not within the defined catalytic motifs. 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 (0.001%) allele frequency.' The evidence for this variant shows: it is absent from gnomAD, 1000 Genomes, ExAC and other large population databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for a recessive disorder.' The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans observations are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions 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, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Missense change at an amino acid residue where a different missense change is known to be pathogenic.' The evidence for this variant shows: it affects splicing and is 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: '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.' The evidence for this variant shows: no de novo observations are reported. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Strong: Co-segregation with disease in ≥7 meioses across ≥2 families.' The evidence for this variant shows: no segregation data are provided. 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 low rate of benign missense variation and where missense is a common mechanism.' The evidence for this variant shows: it is a splice site change, not missense. 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; for splicing variants, concordance of SpliceAI and VarSeak.' The evidence for this variant shows: SpliceAI predicts donor loss score 0.99 and acceptor loss score 0.91, indicating a high likelihood of splicing disruption. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Phenotype is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: patient phenotype or family history is not provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic but evidence is not available for independent evaluation.' The evidence for this variant shows: ClinVar lists this variant as Pathogenic from three clinical laboratories without underlying data. 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: gnomAD Filtering allele frequency >0.00056 (0.056%).' 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: gnomAD Filtering 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: Observed homozygous in a healthy or PHTS-unaffected individual.' 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: Functional studies show no damaging effect; for splicing variants, splicing assay demonstrates no impact.' The evidence for this variant shows: no functional splicing assays performed. 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 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 a gene where only loss-of-function causes disease.' The evidence for this variant shows: it is a splice site variant predicted to cause LOF. 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 or likely pathogenic PTEN variant OR at least three observations in cis.' The evidence for this variant shows: no such 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 deletions/insertions in a repetitive region without known function.' The evidence for this variant shows: it is an intronic splice site change. 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; for splicing variants, concordance of SpliceAI and VarSeak.' 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, 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 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: 'Reputable source reports variant as benign but evidence is not available.' The evidence for this variant shows: no benign assertions in reputable databases. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting: A synonymous or intronic variant at or beyond +7/-21 with no predicted impact.' The evidence for this variant shows: it is at the +1 position, critical for splicing. Therefore, this criterion is not applied.