PTEN c.634+4dup, p.?
NM_000314.8:c.634+4dup
Variant of Uncertain Significance (VUS)
The NM_000314.8:c.634+4dup variant is an intronic duplication predicted to affect splicing by SpliceAI but lacking corroborative functional or clinical data. It is absent from population databases (PM2_Supporting), and no other criteria can be applied. The evidence is insufficient to classify as pathogenic or benign, resulting in a final classification of VUS.
ACMG/AMP Criteria Applied
PM2
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+4dup
Protein Change
?
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+4dup
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
Functional Summary
The PTEN 634+4dup variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN PVS1 decision tree, the rule/finding for PVS1 is: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion)". The evidence for this variant shows: c.634+4dup affects the +4 intronic position, outside the canonical +1/+2 splice sites. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant at the canonical splice positions.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding 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 known pathogenic variant at the same nucleotide or amino acid. Therefore, this criterion is not applied due to absence of a previously established pathogenic variant at the same site.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS2 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 data on de novo status. Therefore, this criterion is not applied because de novo confirmation data are unavailable.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN pre-processing, the finding for PS3 is: "The PTEN 634+4dup variant has not been functionally characterized, and its biological significance remains unknown." The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied due to lack of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls or probands with specificity score ≥4." The evidence for this variant shows: no case-level or cohort data. Therefore, this criterion is not applied due to absence of case or prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule/finding for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain: residues in catalytic motifs 90-94, 123-130, 166-168." The evidence for this variant shows: position +4 intronic site, outside defined functional domains. Therefore, this criterion is not applied because the variant is not within a known mutational hot spot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule/finding 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: allele frequency 0% in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no information on allelic phase or trans observations. Therefore, this criterion is not applied due to lack of trans-phase data.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines for PM4, the rule/finding 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: a single-nucleotide duplication in intron. Therefore, this criterion is not applied because it does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5, the rule/finding 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: intronic duplication, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM6 is: "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: no de novo information. Therefore, this criterion is not applied due to missing de novo data.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PP1, the rule/finding is: "Co-segregation with disease in multiple affected family members, with ≥3-4 meioses observed." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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: intronic duplication, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for PP3, the rule/finding is: "Multiple lines of computational evidence support a deleterious effect. Splicing variants: Concordance of SpliceAI and VarSeak." The evidence for this variant shows: only SpliceAI prediction available. Therefore, this criterion is not applied because concordant predictions from multiple splice algorithms are not present.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source recently reports variant as pathogenic but the evidence is not available for independent evaluation." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1, the rule/finding is: "gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1, the rule/finding is: "gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows: allele frequency 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2, the rule/finding is: "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.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3, the rule/finding 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. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for BS4, the rule/finding 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/finding for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: intronic duplication. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines for BP2, the rule/finding is: "Observed in trans with a pathogenic or likely pathogenic PTEN variant or at least three observations in cis with different pathogenic variants." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines for BP3, the rule/finding is: "In-frame insertions/deletions in a repetitive region without known function." The evidence for this variant shows: single-nucleotide duplication at +4. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for BP4, the rule/finding is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: in silico prediction supports impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines for BP5, the rule/finding is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source reports variant as benign but evidence is not available." The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for BP7, the rule/finding is: "A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact." The evidence for this variant shows: intronic position +4. Therefore, this criterion is not applied.