PTEN c.634+2_634+3insGC, p.Splice_Site
NM_000314.8:c.634+2_634+3insGC
Variant of Uncertain Significance (VUS)
The variant c.634+2_634+3insGC in PTEN disrupts a canonical splice donor site, warranting PVS1 (Very Strong). It is absent from population databases (PM2 Supporting) and in silico models predict splicing disruption (PP3 Supporting). No contradictory or additional data mitigate this evidence. The combination of one Very Strong and two Supporting criteria leads to a final classification of Likely Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PM2
PP3
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+2_634+3insGC
Protein Change
Splice
Location
Exon 6
(Exon 6 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.634+2_634+3insGC
Active Tracks
ConservationRefSeqClinVargnomAD
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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
Unknown
Publications (0)
No publication details.
Clinical Statement
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
Unknown
PP3 Applied
No
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 Use PTEN PVS1 decision tree". The evidence for this variant shows: an insertion at the canonical +2 splice donor site (c.634+2_634+3insGC) predicted to abolish normal splicing and cause loss of function in PTEN, a known LoF disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant disrupts a canonical splice site in a gene where loss of function is established as pathogenic.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "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: no previously reported pathogenic variant at this splice junction resulting in the same effect. Therefore, this criterion is not applied because there is no known pathogenic variant at the same site.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 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 inheritance data available. Therefore, this criterion is not applied because de novo status has not been demonstrated.
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 well-established in vitro or in vivo functional assays (e.g., RNA or mini-gene) demonstrating an impact on splicing or protein function. Therefore, this criterion is not applied because functional data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: Probands with specificity score 4-15.5 OR prevalence significantly increased in affected vs. controls." The evidence for this variant shows: no case data or proband specificity score available. Therefore, this criterion is not applied because there is no evidence of increased prevalence in affected individuals.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Located in a mutational hot spot and/or critical and well-established functional domain (e.g., residues 90-94, 123-130, 166-168)." The evidence for this variant shows: the change is intronic at +2/+3, outside defined catalytic motifs. Therefore, this criterion is not applied because the variant is not within a documented functional hotspot.
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 in gnomAD." The evidence for this variant shows: not found in gnomAD or other control databases (MAF=0%). 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 VCEP guidelines, the rule for PM3 is: "Moderate For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PTEN disease is autosomal dominant and there is no trans observation. Therefore, this criterion is not applied because PM3 is not relevant for autosomal dominant inheritance.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region." The evidence for this variant shows: an intronic insertion that does not change protein length directly. Therefore, this criterion is not applied because there is no in-frame protein change.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate 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: it is not a missense variant. Therefore, this criterion is not applied because PM5 applies only to missense changes.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Moderate Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no inheritance information. Therefore, this criterion is not applied because de novo status is not assumed or reported.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied because segregation information is unavailable.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Missense variant in a gene with low rate of benign missense variation and where missense variants are a common disease mechanism." The evidence for this variant shows: it is an intronic splice variant, not missense. Therefore, this criterion is not applied because PP2 applies only to missense variants.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting 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 donor loss score of 0.99 and acceptor loss score of 0.91 predicting high impact on splicing. Therefore, this criterion is applied at Supporting strength because in silico models concordantly predict disruption of normal splicing.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting Phenotype specific for disease with single genetic etiology." The evidence for this variant shows: no patient phenotype data provided. Therefore, this criterion is not applied because phenotype specificity cannot be assessed.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied because no external pathogenic assertion exists.
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: absent from gnomAD. Therefore, this criterion is not applied because allele frequency is not above the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong gnomAD filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied because allele frequency does not meet BS1.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied because there are no healthy homozygote data.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong 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, this criterion is not applied because no assay data support absence of damage.
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 family segregation data. Therefore, this criterion is not applied because segregation evidence is not available.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Missense variant in a gene for which truncating variants are known mechanism." The evidence for this variant shows: it is a splice variant, not missense. Therefore, this criterion is not applied because BP1 applies only to missense variants.
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 cis/trans phase data. Therefore, this criterion is not applied because there is no information on co-occurrence.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting In-frame deletions/insertions in a repetitive region without known function." The evidence for this variant shows: an intronic insertion not in a repeat region. Therefore, this criterion is not applied because BP3 does not apply.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: computational tools predict high impact on splicing. Therefore, this criterion is not applied because in silico evidence indicates deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no case reports with alternate molecular diagnoses. Therefore, this criterion is not applied because no such case data exist.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Reputable source reports variant as benign without evidence." The evidence for this variant shows: not reported in ClinVar or other sources. Therefore, this criterion is not applied because no benign assertions are available.
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 splicing impact." The evidence for this variant shows: insertion at +2/+3 predicted to disrupt splicing. Therefore, this criterion is not applied because the variant affects the canonical splice site.