PTEN c.516G>T, p.Arg172Ser
NM_000314.8:c.516G>T
Variant of Uncertain Significance (VUS)
R172S is a missense variant absent from population databases (PM2_Supporting) but lacks supportive computational (PP3), functional (PS3), segregation, or case data. Based on VCEP-specified ACMG criteria, evidence is insufficient for pathogenic or benign classification, resulting in 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.516G>T
Protein Change
R172S
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
Genome Browser
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HGVS InputNM_000314:c.516G>T
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
No evidence of other pathogenic variants at position 172 in gene PTEN
Functional Summary
The PTEN R172S variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.66
0.66
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Pathogenic
PP3 Applied
No
Additional Predictors
Pathogenic:
sift: Dmutationtaster: Dfathmm: Dprovean: Dmetasvm: Dmetalr: Dprimateai: Ddeogen2: D
Benign:
CADD: 3.80polyphen_prediction: benign
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Use PTEN PVS1 decision tree to evaluate predicted loss-of-function variants in a gene where LOF is a known mechanism of disease." The evidence for this variant shows: R172S is a missense change, not a null variant. Therefore, this criterion is not applied because the variant does not meet the LOF requirement.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP 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 shows: no previously established pathogenic R172S variant reported. Therefore, this criterion is not applied due to lack of matching established pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong: two proven OR four assumed de novo observations... Strong: de novo (both maternity and paternity confirmed)." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied because de novo status cannot be confirmed.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "Score (0.0011) did not meet threshold (-1.11) for PS3_Moderate." The evidence for this variant shows: functional assay score did not reach the threshold. Therefore, this criterion is not applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: specificity score 4-15.5 or significant enrichment in cases; Moderate: score 2-3.5; Supporting: score 1-1.5." The evidence for this variant shows: no case or enrichment data available. Therefore, this criterion is not applied due to lack of proband frequency data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical functional domain: catalytic motifs include residues 90-94, 123-130, 166-168." The evidence for this variant shows: R172 lies outside these defined motifs. Therefore, this criterion is not applied because the variant is not in a critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent in population databases at <0.00001 allele frequency in gnomAD or another large database." The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PTEN-related conditions are dominant and no trans data present. Therefore, this criterion is not applied because it is not relevant for a dominant gene and no compound heterozygosity data exist.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels in non-repeat regions or stop-loss variants." The evidence for this variant shows: R172S is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Missense change at a residue where a different missense change determined to be pathogenic has been seen." The evidence for this variant shows: no other pathogenic missense at residue 172 reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo observations without paternity/maternity confirmation." The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Support: co-segregation in 3-4 meioses; Moderate: 5-6; Strong: ≥7." The evidence for this variant shows: no family 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 in a gene with low rate of benign missense and where missense is common mechanism." The evidence for this variant shows: insufficient gene-level benign missense rate data to apply. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting: Multiple lines of computational evidence; REVEL score > 0.7 for missense variants." The evidence for this variant shows: REVEL score is 0.66, below threshold. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Phenotype or family history highly specific for a disorder with single genetic etiology." The evidence for this variant shows: no patient phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source classifies variant as pathogenic without available evidence." The evidence for this variant shows: no such external classification. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: gnomAD filtering AF >0.00056." The evidence for this variant shows: AF=0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: AF 0.000043–0.00056; Supporting: AF 0.0000043–0.000043." The evidence for this variant shows: AF=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 healthy individual; Supporting: two homozygotes without clinical data." 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: well-established functional studies show no damaging effect." The evidence for this variant shows: no such functional evidence. 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 ≥2 families; Supporting: lack in one family." 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 in a gene where only truncating variants cause disease." The evidence for this variant shows: PTEN disease mechanism includes missense. 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 pathogenic PTEN variant or ≥3 cis observations." The evidence for this variant shows: no cis/trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive region without known function." The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: multiple computational lines suggest no impact; REVEL <0.5 for missense." The evidence for this variant shows: mixed predictions and REVEL=0.66. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant in a case with alternate molecular basis for disease." The evidence for this variant shows: no such alternate molecular findings. 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 as benign without evidence." 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, the rule for BP7 is: "Synonymous or intronic variants with no splicing impact." The evidence for this variant shows: it is missense. Therefore, this criterion is not applied.