PTEN c.140G>A, p.Arg47Lys
NM_000314.8:c.140G>A
COSMIC ID: COSM7482313
Likely Pathogenic
NM_000314.8:c.140G>A (p.R47K) in PTEN is classified as Likely Pathogenic based on two Moderate criteria (PS3, PM5) and three Supporting criteria (PM2, PP3, PP5) consistent with ACMG/AMP and VCEP PTEN guidelines.
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.140G>A
Protein Change
R47K
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: R47G
Alternate Identifiers
COSM7482313
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.140G>A
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
2 publications
Likely Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
1 Path
2 LP
2 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to lysine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools with high conservation but a minor amino acid change. (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. p.(Arg47Gly) has been previously reported in a family with Cowden Syndrome (PMID: 11494117) (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. (one case in ClinVar) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Low functional evidence supporting abnormal protein function. Site directed mutagenesis enzymatic assays show reduced phosphate activity. (PMID: 20538496, 25429968) (P) 1102 - Strong phenotype match. (P) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
This variant disrupts the p.Arg47 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11494117; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects PTEN function (PMID: 20538496, 32350270). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 373446). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 47 of the PTEN protein (p.Arg47Lys).
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen expert panel.
Expert Panel Reviews
Likely 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: R47G
PM5 criterion applied.
Functional Summary
The PTEN R47K variant has been functionally characterized. It results in increased lipid phosphatase activity in vitro and maintains protein stability similar to the wild-type. However, it fails to suppress Akt phosphorylation in cell culture and leads to impaired developmental growth in flies, indicating a potential functional impact.
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
0.903
0.903
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
Yes
Additional Predictors
Pathogenic:
sift: Dpolyphen_prediction: probably_damagingmutationtaster: Dfathmm: Dprovean: Dmetasvm: Dmetalr: Dprimateai: Ddeogen2: D
Benign:
CADD: 5.63
Neutral: Show all
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, PVS1 applies to null variants in a gene where loss‐of‐function is a known mechanism. This variant is a missense change (R47K), not a predicted loss‐of‐function. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1, it requires the same amino acid change as a known pathogenic variant. No identical amino acid change to R47K has been established as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS2, it requires confirmed de novo occurrence with parental testing. No de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing guidelines, the rule for PS3_Moderate is: "Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350." The evidence for this variant shows a functional score of -1.3570, which is below the threshold of -1.11. Therefore, this criterion is applied at Moderate strength because the functional assay demonstrates a damaging effect on phosphatase activity.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PS4, it requires case counts or increased prevalence in affected individuals. No case‐level or prevalence data are provided. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PM1, it applies to variants located in critical catalytic motifs (residues 90–94, 123–130, 166–168). R47 is outside these regions. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2, the rule is: "Absent in population databases or present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows it is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM3, it applies to recessive disorders with evidence of trans configuration with a pathogenic variant. No recessive/trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines for PM4, it applies to in‐frame indels causing protein length changes. This is a missense variant, not an indel. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines for PM5, the rule is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before." Other missense changes at residue 47 have been reported as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM6, it requires presumed de novo occurrence without confirmation of parentage. No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PP1, it requires co‐segregation with disease in multiple affected family members. No segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP2, it applies to missense variants in a gene with low benign variation where missense is a common mechanism. PTEN has both truncating and missense pathogenic variants, and benign missense variants exist. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines for PP3, the rule is: "REVEL score > 0.7 for missense variants." The evidence for this variant shows a REVEL score of 0.90. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP4, it applies when the phenotype is highly specific for a single genetic etiology. No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines for PP5, the rule is: "Reputable source reports variant as pathogenic but evidence unavailable." ClinVar and the ClinGen PTEN Expert Panel report this variant as Likely Pathogenic/Pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1, it requires allele frequency >0.056% in gnomAD. The variant is absent. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1, it requires allele frequency between 0.0043% and 0.056% in gnomAD. The variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2, it requires observations of homozygosity in healthy individuals. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3, it requires well‐established functional studies showing no damaging effect. Functional data show a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for BS4, it requires lack of segregation in multiple families. No segregation data are provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP1, it applies to missense variants in genes where only truncating variants cause disease. PTEN pathogenic missense variants are documented. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines for BP2, it requires cis/trans observations with other pathogenic PTEN variants. No such data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP3, it applies to in‐frame indels in repetitive regions. This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for BP4, it requires computational evidence suggesting no impact (REVEL < 0.5). The REVEL score is 0.90. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP5, it applies when an alternate molecular basis for disease is found. No alternate basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP6, it requires a reputable source reporting the variant as benign. No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP7, it applies to synonymous or intronic variants with no splicing impact. This is a missense variant. Therefore, this criterion is not applied.