PTEN c.106G>A, p.Gly36Arg

NM_000314.8:c.106G>A

COSM5135

Classification Summary

Pathogenic

This PTEN G36R missense variant is absent from population databases (PM2_Supporting), has strong computational evidence of deleterious effect (PP3_Supporting), is reported as pathogenic by reputable sources (PP5_Supporting), and has functional studies showing impaired phosphatase activity meeting the PTEN-specific threshold (PS3_Moderate). Together, the evidence supports a Pathogenic classification.

Population Frequency

0.0 in 100,000

Rare

ClinVar Classification

Likely Pathogenic

3 publications

REVEL Score

0.995

Likely Pathogenic

COSMIC Recurrence

15 occurrences

No Criteria Applied

Classification Evidence

Very Strong (PVS)

None applied

Strong (PS/BS)

None applied

Moderate (PM/BA)

PS3

Supporting (PP/BP)

PM2 PP3 PP5

ClinVar COSMIC OncoKB JAX-CKB SpliceAI

Created: 2025-05-15T12:26:59.070717

Detailed Information

Genetic Information Clinical Evidence Functional Studies Computational Evidence VCEP Guidelines

Genetic Information

Gene & Transcript Details

Gene

PTEN

Transcript

                                        
                                            NM_000314.8
                                        
                                                    MANE Select

Total Exons

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.106G>A

Protein Change

G36R

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 36: G36E

Alternate Identifiers

                                    COSM5135
                                

Variant interpretation based on transcript NM_000314.8

Clinical Evidence

Population Frequency

Global Frequency

0.0 in 100,000

Extremely Rare

Global: 0.0%

0.0005%

0.001%

0.01%

0.05%

1%+

ACMG Criteria Applied

PM2

This variant is not present in gnomAD (PM2 criteria applies).

ClinVar 2025-05-15T12:25:26.217404

Classification

3 publications

Likely Pathogenic

Based on 4 submitter reviews in ClinVar

Submitter Breakdown

1 Path

3 LP

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Publications

3 publications

Show publication details

PMID: 10772390

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10772390, 32442409, 17942903]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 32350270].

PMID: 10772390

The p.G36R variant (also known as c.106G>A), located in coding exon 2 of the PTEN gene, results from a G to A substitution at nucleotide position 106. The glycine at codon 36 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in one individual with clinical features of Cowden syndrome, including: trichilemmomas, oral papillomatosis, acral keratosis, breast cancer, hypothyroidism, gastrointestinal polyps, macrocephaly, and uterine fibroids (Celebi JT et al. Exp. Dermatol., 2000 Apr;9:152-6). In addition, this alteration was detected in 1 of 802 subjects undergoing PTEN genetic testing; however, individual phenotype information was not provided (Pilarski R et al. J. Med. Genet., 2011 Aug;48:505-12). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). In a functional study using a yeast-based assay, this variant demonstrated severely reduced phosphatase activity when compared to wild type PTEN and was similar to the catalytic dead control (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov;20:4132-42). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

PMID: 10772390

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 36 of the PTEN protein (p.Gly36Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Cowden syndrome (PMID: 10772390, 32442409; Invitae). ClinVar contains an entry for this variant (Variation ID: 1334551). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 17942903, 21828076, 25875300). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Publication Summary:

- **PMID: 25741868**: This variant is classified as pathogenic based on ACMG guidelines, with supporting evidence from multiple criteria including PS3, PP2, PP3, PM1, PM2, and PS4_Supporting. - **PMID: 10772390**: This variant has been reported in multiple individuals with clinical features of gene-specific disease, supporting its classification as likely pathogenic. - **PMID: 32442409**: This variant has been observed in individuals with clinical features of Cowden syndrome, contributing to its classification as likely pathogenic. - **PMID: 17942903**: Experimental studies have shown that this missense change affects PTEN function, supporting its classification as likely pathogenic. - **PMID: 32350270**: Functional studies indicate this variant impacts protein function, contributing to its classification as likely pathogenic. - **PMID: 21828076**: This variant has been observed in individuals with clinical features of Cowden syndrome, supporting its classification as likely pathogenic. - **PMID: 25875300**: Experimental studies have shown that this missense change affects PTEN function, supporting its classification as likely pathogenic. - **PMID: 29706350**: Functional studies using a yeast-based assay demonstrated severely reduced phosphatase activity for this variant, supporting its classification as likely pathogenic.

Clinical Statement

This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories) and as Likely pathogenic (3 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

COSMIC

COSMIC ID

COSM5135

Recurrence

15 occurrences

PM1 Criteria

Not Applied

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Functional Domain

Cancer Hotspots

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 36: G36E

PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Functional Studies

Functional Impact

OncoKB JAX-CKB

Summary

The PTEN G36R variant has been functionally characterized and shown to be damaging. It results in impaired nuclear localization and loss of phosphatase activity, as demonstrated in yeast models.

Computational Evidence

Pathogenicity Predictions

REVEL Score

0.995

Likely Benign 0.0

Uncertain (Low) 0.2

Uncertain (Med) 0.5

Likely Pathogenic 0.75

REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)

Predictor Consensus

Pathogenic

PP3 Applied

Yes

Additional Predictors

Pathogenic:

sift: D polyphen_prediction: probably_damaging mutationtaster: D mutationassessor: H fathmm: D provean: D metasvm: D metalr: D primateai: D deogen2: D

Benign:

CADD: 5.86

SpliceAI Scores Window: ±500bp

Effect Type	Score	Position
- Acceptor Loss	0.17	13 bp
- Donor Loss	0.14	58 bp
+ Acceptor Gain	0.02	2 bp
+ Donor Gain	0.0	2 bp

High impact (≥0.5)

Medium impact (0.2-0.49)

Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria VCEP Guidelines

PVS1

PVS1 (Not Applied) Strength Modified

According to VCEP guidelines: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific." The variant is a missense change (G36R), not predicted to cause loss of function per the PVS1 decision tree. Therefore, this criterion is not applied.

PS1

PS1 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Strength: Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change... Modification Type: Disease-specific." There is no report of a G36R change from a different nucleotide. Therefore, PS1 is not applied.

PS2

PS2 (Not Applied) Strength Modified

According to VCEP guidelines: "Very Strong Strength: Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations...; Strong Strength: Strong De novo (both maternity and paternity confirmed) observation..." No de novo or parental testing data are available. Therefore, PS2 is not applied.

PS3

PS3 (Moderate) Strength Modified

According to PTEN Pre-processing finding: "Applied PS3_Moderate (Score -2.6930 < -1.11)". The PTEN G36R variant shows a phosphatase activity score of -2.6930, which meets the PTEN-specific threshold. Therefore, PS3 is applied at Moderate strength.

PS4

PS4 (Not Applied) Strength Modified

According to VCEP guidelines: "Very Strong Strength... Probands with specificity score ≥16...; Strong Strength... 4-15.5...; Moderate Strength... 2-3.5...; Supporting Strength... 1-1.5." No case or proband data are available. Therefore, PS4 is not applied.

PM1

PM1 (Not Applied) Strength Modified

According to VCEP guidelines: "Moderate Strength: Moderate Located in a mutational hotspot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168." Codon 36 is outside these motifs. Therefore, PM1 is not applied.

PM2

PM2 (Supporting) Strength Modified

According to VCEP guidelines: "Supporting Strength: Supporting Absent in population Databases present at <0.00001..." The variant is absent from gnomAD and other large population databases. Therefore, PM2 is applied at Supporting strength.

PM3

PM3 (Not Applied) Strength Modified

According to standard ACMG guidelines: PM3 applies to recessive disorders when detected in trans with a pathogenic variant. PTEN-associated disease is autosomal dominant and no trans data are available. Therefore, PM3 is not applied.

PM4

PM4 (Not Applied) Strength Modified

According to VCEP guidelines: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions..." The variant is a missense substitution without length change. Therefore, PM4 is not applied.

PM5

PM5 (Not Applied) Strength Modified

According to VCEP guidelines: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before..." There is no known different pathogenic missense at residue 36. Therefore, PM5 is not applied.

PM6

PM6 (Not Applied) Strength Modified

According to VCEP guidelines: "Very Strong Strength... Two proven OR four assumed... de novo observations without confirmation; Strong Strength... two presumed de novo...; Moderate Strength... assumed de novo without confirmation." No de novo data are available. Therefore, PM6 is not applied.

PP1

PP1 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Strength: Strong Co-segregation with disease in multiple affected family members, with ≥7 meioses...; Moderate Strength: 5-6 meioses...; Supporting Strength: 3-4 meioses..." No segregation data are available. Therefore, PP1 is not applied.

PP2

PP2 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." Specific data on benign missense rate in PTEN were not provided. Therefore, PP2 is not applied.

PP3

PP3 (Supporting)

According to VCEP guidelines: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect... Missense variants: REVEL score > 0.7." The REVEL score for G36R is 0.99. Therefore, PP3 is applied at Supporting strength.

PP4

PP4 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting Phenotype specific for disease with single genetic etiology..." No clinical phenotype or family history was provided. Therefore, PP4 is not applied.

PP5

PP5 (Supporting)

According to standard ACMG guidelines: "Supporting Reputable source recently reports variant as pathogenic..." ClinVar and the ClinGen PTEN Expert Panel classify this variant as Pathogenic/Likely Pathogenic. Therefore, PP5 is applied at Supporting strength.

BA1

BA1 (Not Applied) Strength Modified

According to VCEP guidelines: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056". The variant is absent in gnomAD. Therefore, BA1 is not applied.

BS1

BS1 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Strength: allele frequency 0.000043-0.00056; Supporting Strength: 0.0000043-0.000043". The variant is absent. Therefore, BS1 is not applied.

BS2

BS2 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Strength: Observed homozygous in healthy individual...; Supporting Strength: Two homozygous observations..." No homozygous observations reported. Therefore, BS2 is not applied.

BS3

BS3 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Strength: Well-established in vitro or in vivo functional studies shows no damaging effect; Supporting Strength: phosphatase activity >0..." Functional studies show damaging effect. Therefore, BS3 is not applied.

BS4

BS4 (Not Applied) Strength Modified

According to VCEP guidelines: "Strong Strength: Lack of segregation in two or more families; Supporting Strength: Lack of segregation in one family." No segregation data. Therefore, BS4 is not applied.

BP1

BP1 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting Missense variant in a gene where only truncating variants cause disease." PTEN disease mechanism includes missense variants. Therefore, BP1 is not applied.

BP2

BP2 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting Observed in trans with a pathogenic PTEN variant OR in cis with three or more..." No phase or cis/trans data. Therefore, BP2 is not applied.

BP3

BP3 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting In-frame indels in a repetitive region..." The variant is missense. Therefore, BP3 is not applied.

BP4

BP4 (Not Applied) Strength Modified

According to VCEP guidelines: "Supporting Multiple lines of computational evidence suggest no impact... Missense variants: REVEL score < 0.5." REVEL is 0.99 indicating deleterious effect. Therefore, BP4 is not applied.

BP5

BP5 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting Variant found in a case with an alternate molecular basis for disease..." No such case or alternate molecular basis provided. Therefore, BP5 is not applied.

BP6

BP6 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting Reputable source reports benign." No reputable source reports this variant as benign. Therefore, BP6 is not applied.

BP7

BP7 (Not Applied) Strength Modified

According to standard ACMG guidelines: "Supporting A synonymous or intronic variant at or beyond +7/-21 with no splicing impact predicted." This is a missense variant. Therefore, BP7 is not applied.

LYFE SCIENCES

PTEN c.106G>A, p.Gly36Arg

Classification Summary

Genetic Information

Clinical Evidence

Functional Studies

Computational Evidence

VCEP Guidelines