PTEN c.139A>G, p.Arg47Gly
NM_000314.8:c.139A>G
COSMIC ID: COSM28887
Likely Pathogenic
R47G in PTEN is classified as Likely Pathogenic based on PTEN-specific functional evidence (PS3_Moderate), absence from controls (PM2_Supporting), pathogenic precedent at the same residue (PM5_Moderate), and supportive computational (PP3) and reputable source (PP5) evidence.
ACMG/AMP Criteria Applied
PS3
PM2
PM5
PP3
PP5
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.139A>G
Protein Change
R47G
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 47: R47K
Alternate Identifiers
COSM28887
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.139A>G
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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
3 publications
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 25429968). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 47 of the PTEN protein (p.Arg47Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN-related conditions (PMID: 11494117; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189401). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function.
The p.R47G pathogenic mutation (also known as c.139A>G), located in coding exon 2 of the PTEN gene, results from an A to G substitution at nucleotide position 139. The arginine at codon 47 is replaced by glycine, an amino acid with dissimilar properties. Functional assays demonstrated reduced phosphatase activity for p.R47G compared to wild type PTEN (Wang Q et al. J. Mol. Graph. Model., 2010 Aug;29:102-14; Wei Y et al. J. Biol. Chem., 2015 Jan;290:1592-606; Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). In addition, this alteration was reported in a cohort of 21 families with Cowden or Bannayan-Riley-Ruvalcaba syndrome in a family with GI polyps, multiple fibroadenomas of the breast, Hashimoto's thyroiditis and goiter, lipomas, and papules of the oral mucosa (Marsh DJ et al. Neoplasia;3:236-44). This variant has also been identified, one of which was a de novo occurrence, in children with clinical features of PTEN hamartoma tumor syndrome including penile freckling and/or macrocephaly with developmental delay (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PTEN c.139A>G (p.Arg47Gly) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) ClinVar Organization ID: 26957) PS3: Phosphatase activity <50% of wild type (PMID 20538496, 25429968, 29706350) PM2: Absent in large sequenced populations (PMID 27535533) PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor(s) ClinVar Organization ID: 26957)
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen expert panel.
Expert Panel Reviews
Pathogenic
Clingen PTEN Variant Curation Expert Panel, Clingen
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
ClinVar reports other pathogenic variants at position 47: R47K
PM5 criterion applied.
Functional Summary
The PTEN R47G 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
0.958
0.958
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.37
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: PTEN PVS1 decision tree for null variants (nonsense, frameshift, canonical ±1–2 splice sites, initiation codon). The evidence for this variant shows: R47G is a missense change, not a predicted null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not introduce loss of function per PVS1 decision tree.
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: R47G is a novel amino acid substitution with no prior identical pathogenic change reported. Therefore, this criterion is not applied at Not Applied strength because there is no known identical amino acid change established as pathogenic.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. The evidence for this variant shows: No de novo occurrence data are available. Therefore, this criterion is not applied at Not Applied strength due to lack of confirmed de novo evidence.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3_Moderate is: phosphatase activity score -2.3377 < threshold -1.11 per Mighell et al. 2018. The evidence for this variant shows: high-confidence functional score of -2.3377 indicating significantly reduced PTEN phosphatase activity. Therefore, this criterion is applied at Moderate strength because the functional assay meets the PTEN-specific PS3_moderate threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: Increased prevalence of variant in affected individuals or proband specificity score ≥4. The evidence for this variant shows: No case/control or proband specificity data available. Therefore, this criterion is not applied at Not Applied strength due to absence of prevalence or proband evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: Located in a mutational hotspot or critical functional domain (residues 90–94, 123–130, 166–168). The evidence for this variant shows: R47G lies outside defined catalytic motifs/hotspots. Therefore, this criterion is not applied at Not Applied strength because the residue is not within a PTEN hotspot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: Absent in population databases or present at <0.001% allele frequency. The evidence for this variant shows: Not observed in gnomAD or other large population cohorts (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: Detected in trans with a pathogenic variant for a recessive disorder. The evidence for this variant shows: PTEN-associated disease is autosomal dominant and no in trans data apply. Therefore, this criterion is not applied at Not Applied strength because PM3 is not relevant for autosomal dominant PTEN.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: Protein length changes due to in-frame indels or stop-loss in non-repeat regions. The evidence for this variant shows: R47G is a missense substitution without length alteration. Therefore, this criterion is not applied at Not Applied strength because there is no protein length change.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: Novel missense change at a residue where a different missense change has been established pathogenic, with BLOSUM62 score equal to or less than the known variant. The evidence for this variant shows: Other pathogenic missense variants at residue R47 have been reported and R47G BLOSUM62 score meets the threshold. Therefore, this criterion is applied at Moderate strength because the residue has known pathogenic substitutions and the biochemical change is at least as destabilizing.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: Assumed de novo without parental confirmation. The evidence for this variant shows: No de novo assumption data. Therefore, this criterion is not applied at Not Applied strength due to absence of assumed de novo information.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: Co-segregation with disease in affected family members. The evidence for this variant shows: No segregation data available. Therefore, this criterion is not applied at Not Applied strength because there are no family segregation studies.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: Missense variant in a gene with low rate of benign missense variation where missense is a common disease mechanism. The evidence for this variant shows: PTEN does have pathogenic missense variants but gene-specific acceptance of PP2 is not defined. Therefore, this criterion is not applied at Not Applied strength due to lack of explicit gene-specific guidance.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: REVEL score >0.7 for missense variants. The evidence for this variant shows: REVEL = 0.96, exceeding the 0.7 threshold. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict deleterious effect.
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 shows: No detailed phenotype or family history provided. Therefore, this criterion is not applied at Not Applied strength due to lack of clinical specificity data.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: Reputable source reports variant as pathogenic but evidence is unavailable. The evidence for this variant shows: ClinVar entries (2 labs) and ClinGen PTEN Expert Panel classify as Pathogenic without primary data. Therefore, this criterion is applied at Supporting strength because reputable sources report pathogenicity.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: Allele frequency >0.056% in gnomAD. The evidence for this variant shows: Absent from gnomAD. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is zero, far below BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: Allele frequency between 0.0043% and 0.056% in gnomAD. The evidence for this variant shows: Absent from population databases. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is below BS1 threshold.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: Observed homozygous in healthy individuals. The evidence for this variant shows: No homozygous observations reported. Therefore, this criterion is not applied at Not Applied strength because there are no homozygous healthy occurrences.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: Well-established functional studies show no damaging effect. The evidence for this variant shows: Functional data indicate damaging effect (reduced phosphatase activity). Therefore, this criterion is not applied at Not Applied strength because the variant is functionally deleterious.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: Lack of segregation in affected members. The evidence for this variant shows: No segregation data. Therefore, this criterion is not applied at Not Applied strength due to absence of non-segregation evidence.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: Missense variant in a gene where only truncating variants cause disease. The evidence for this variant shows: PTEN pathogenic missense variants are known. Therefore, this criterion is not applied at Not Applied strength because missense is an established mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: Observed in trans with a pathogenic PTEN variant or multiple in cis. The evidence for this variant shows: No in trans or in cis observations with other PTEN variants. Therefore, this criterion is not applied at Not Applied strength due to lack of phase data.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: In-frame indels in repetitive regions. The evidence for this variant shows: R47G is a missense substitution. Therefore, this criterion is not applied at Not Applied strength because it is not an in-frame indel.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: REVEL <0.5 for missense variants. The evidence for this variant shows: REVEL = 0.96, indicating deleterious effect. Therefore, this criterion is not applied at Not Applied strength because in silico predictions support pathogenicity.
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 shows: No alternate molecular basis reported. Therefore, this criterion is not applied at Not Applied strength due to lack of conflicting molecular findings.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: Reputable source reports variant as benign without available evidence. The evidence for this variant shows: No benign classifications by reputable sources. Therefore, this criterion is not applied at Not Applied strength because no benign assertions exist.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: Synonymous or intronic variant with no splicing impact. The evidence for this variant shows: R47G is a missense change. Therefore, this criterion is not applied at Not Applied strength because BP7 applies only to silent or intronic variants.