PTEN c.516delG, p.Arg172SerfsTer11
NM_000314.8:c.516delG
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Pathogenic
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 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.516delG
Protein Change
R172Sfs*11
Location
Exon 6
(Exon 6 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 172 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 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
No evidence of other pathogenic variants at position 172 in gene PTEN
Functional Studies
Summary
The PTEN R172Sfs*11 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have shown that such truncating mutations are oncogenic, increasing genome fragility due to the failure of PTEN to associate with chromosomal centromeres.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 states: 'PVS1 applied - truncating variant (exon information unavailable)'. The evidence for this variant shows that NM_000314.8:c.516delG is a frameshift (truncating) mutation in PTEN, a gene where loss‐of‐function is a known mechanism of disease, and it is not the last exon. Therefore, this criterion is applied at Very Strong strength because the truncating nature meets the PTEN-specific decision tree.
PS3
PS3 (Strong)
According to PTEN Pre-processing guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows that functional studies demonstrate that the R172Sfs*11 variant causes loss of PTEN phosphatase function, leading to oncogenic effects. Therefore, this criterion is applied at Strong strength because the pre-processing functional evidence is clear and specific for PTEN.
PM2
PM2 (Supporting)
Strength Modified
According to Standard ACMG guidelines (and supported by VCEP modifications for PM2), the rule for PM2 is: 'Absent in population databases present at <0.00001 (0.001%) allele frequency'. The evidence for this variant shows a Minor Allele Frequency of 0% in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
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 that ClinVar has reported the variant as Pathogenic from a clinical laboratory. Therefore, this criterion is applied at Supporting strength because the reputable source provides supportive evidence for pathogenicity.
PS1
PS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant does not show an alternative nucleotide change resulting in the same amino acid substitution. Therefore, this criterion is not applied because the condition is not met.
PS2
PS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PS2 is: 'De novo (with confirmed parentage) occurrence in a patient with the disease'. The evidence for this variant does not provide any information regarding de novo occurrence. Therefore, this criterion is not applied because the required de novo data is missing.
PS4
PS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PS4 is: 'Prevalence of the variant in affected individuals is significantly increased compared with controls'. The evidence for this variant does not provide any case-control data. Therefore, this criterion is not applied because there is no supporting prevalence data.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines for PM1, the rule is: 'Located in a mutational hot spot and/or critical and well-established functional domain'. The evidence for this variant does not specify location within a designated catalytic motif or hotspot. Therefore, this criterion is not applied because the variant location is not demonstrated to be within a critical domain.
PM3
PM3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PM3 is used for recessive disorders to indicate detection in trans with a pathogenic variant. The evidence for this variant does not involve recessive inheritance or trans occurrence. 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 a frameshift truncation rather than an in-frame change or protein extension. 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 determined to be pathogenic has been seen before'. The evidence for this variant does not involve a missense change but rather a frameshift mutation. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PM6 is related to presumed de novo occurrence in a patient with the disease. The evidence for this variant does not provide any de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant does not include segregation data. 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 that has a low rate of benign missense variation where missense variants are a common mechanism of disease'. The evidence for this variant is not a missense change but a truncating mutation. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. The evidence for this variant shows inconclusive in silico predictions (with SpliceAI showing no splicing impact) and does not consistently support a deleterious computational outcome. Therefore, this criterion is not applied.
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 does not include detailed phenotype or family history data. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Allele frequency in gnomAD is greater than the stand-alone threshold'. The evidence for this variant shows a frequency of 0% in gnomAD, which is well below the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Allele frequency in gnomAD falls within a benign range'. The evidence for this variant shows a frequency of 0%, which does not satisfy benign frequency thresholds. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Observation in the homozygous state in healthy individuals'. The evidence for this variant does not report any homozygous occurrences in unaffected individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS3 is: 'Well-established in vitro or in vivo functional studies show no damaging effect on protein function'. The evidence for this variant demonstrates a damaging effect on PTEN function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant does not include segregation data in unaffected individuals. 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 for which primarily truncating variants are known to cause disease'. Although PTEN is sensitive to truncating mutations, this rule is typically applied to favor benign interpretation for missense variants. The evidence for this variant is of a truncating nature. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP2 is: 'Observation in trans with a pathogenic variant or multiple observations in cis with other pathogenic variants'. The evidence for this variant does not include such phase information. 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 a known function'. The evidence for this variant is not an in-frame change but a frameshift deletion. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to Standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on the gene or gene product'. The evidence for this variant shows that although general in silico predictions are inconclusive, SpliceAI analysis reports a maximum score of 0, indicating no splicing impact. Therefore, this criterion is applied at Supporting strength as benign computational evidence.
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 does not include another clear molecular cause for the disease phenotype. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP6 is: 'Reputable source has reported the variant as benign'. The evidence for this variant shows that the reputable source (ClinVar) reported it as Pathogenic. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP7 is: 'A synonymous or intronic variant with no predicted splicing impact'. The evidence for this variant is a frameshift deletion, not a synonymous or intronic change. Therefore, this criterion is not applied.