Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.5 | Alternative | 8719 nt | 1032–2243 |
| NM_000314.4 | Alternative | 5572 nt | 1032–2243 |
| NM_000314.3 | Alternative | 3416 nt | 1032–2243 |
| NM_000314.6 | Alternative | 8718 nt | 1032–2243 |
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe 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.
"This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.91 | -142 bp |
| Donor Loss (DL) | 0.99 | -1 bp |
| Acceptor Gain (AG) | 0.0 | 3 bp |
| Donor Gain (DG) | 0.0 | 28 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
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: c.634+1G>C affects the canonical +1 splice donor site in PTEN, predicted to abolish normal splicing and result in loss of function in a gene where LOF is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because the variant is an essential splice site change predicted to cause loss of function.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "**Strong Strength**: 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: There is no previously established pathogenic variant at the same nucleotide position in PTEN. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "**Strong Strength**: 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 occurrences have been reported or documented. Therefore, this criterion is not applied.
PS3 (Not Applied)
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 well-established in vitro or in vivo functional studies are available to assess its impact on splicing or protein function. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "**Strong Strength**: Strong The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.". The evidence for this variant shows: No case-control data or proband series have been reported to demonstrate increased prevalence in affected individuals. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "**Moderate Strength**: Moderate 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 is a splice site variant outside of these defined catalytic motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "**Supporting Strength**: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).". The evidence for this variant shows: It is absent from gnomAD and other large population databases. Therefore, this criterion is applied at Supporting strength because the variant is not observed in large population cohorts.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "**Moderate Strength**: Moderate For recessive disorders, detected in trans with a pathogenic variant.". The evidence for this variant shows: PTEN is associated with autosomal dominant disease and no trans observation with another pathogenic PTEN variant is available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "**Moderate Strength**: Moderate 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 variant predicted to lead to truncation or exon skipping rather than an in-frame change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "**Moderate Strength**: Moderate 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 not a missense variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "**Moderate Strength**: Moderate Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history.". The evidence for this variant shows: There are no de novo observations reported. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "**Supporting Strength**: Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.". The evidence for this variant shows: No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "**Supporting Strength**: Supporting 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 not a missense variant. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "**Supporting Strength**: Supporting 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 loss of the donor site with a score of 0.99. Therefore, this criterion is applied at Supporting strength because computational tools strongly predict disruption of normal splicing.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "**Supporting Strength**: Supporting 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 patient phenotype information is provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "**Supporting Strength**: Supporting 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: ClinVar entries from three clinical laboratories classify c.634+1G>C as Pathogenic. Therefore, this criterion is applied at Supporting strength because multiple reputable sources report it as pathogenic without accessible primary evidence.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "**Stand Alone Strength**: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%).". The evidence for this variant shows: It is absent from gnomAD, not exceeding the frequency threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "**Strong Strength**: Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).". The evidence for this variant shows: It is absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "**Strong Strength**: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual...". The evidence for this variant shows: No healthy homozygous observations have been reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "**Strong Strength**: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA or mini-gene splicing assay demonstrating no impact.". The evidence for this variant shows: No functional or splicing assays demonstrating lack of effect are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "**Strong Strength**: Strong Lack of segregation in affected members of two or more families.". The evidence for this variant shows: No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "**Supporting Strength**: Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease.". The evidence for this variant shows: It is a splice site variant, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "**Supporting Strength**: 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 data on cis or trans observations with other PTEN variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "**Supporting Strength**: Supporting In-frame deletions/insertions in a repetitive region without a known functional domain.". The evidence for this variant shows: It is a splice site variant, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "**Supporting Strength**: Supporting 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: SpliceAI predicts high-impact donor loss. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "**Supporting Strength**: Supporting Variant found in a case with an alternate molecular basis for disease...". The evidence for this variant shows: No alternate molecular diagnosis has been reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "**Supporting Strength**: Supporting Reputable source reports variant as benign but evidence not available.". The evidence for this variant shows: No reputable source reports it as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "**Supporting Strength**: Supporting A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact.". The evidence for this variant shows: It is at position +1, not beyond +7, and predicted to disrupt splicing. Therefore, this criterion is not applied.