NM_000314.8(PTEN):c.755A>G (p.Asp252Gly) AND PTEN hamartoma tumor syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 14, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000758222.11

Allele description [Variation Report for NM_000314.8(PTEN):c.755A>G (p.Asp252Gly)]

NM_000314.8(PTEN):c.755A>G (p.Asp252Gly)

Gene:

PTEN:phosphatase and tensin homolog [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_000314.8(PTEN):c.755A>G (p.Asp252Gly)

Other names:

NM_000314.6(PTEN):c.755A>G

HGVS:

NC_000010.11:g.87957973A>G
NG_007466.2:g.99535A>G
NM_000314.8:c.755A>GMANE SELECT
NM_001304717.5:c.1274A>G
NM_001304718.2:c.164A>G
NP_000305.3:p.Asp252Gly
NP_001291646.4:p.Asp425Gly
NP_001291647.1:p.Asp55Gly
LRG_311t1:c.755A>G
LRG_311:g.99535A>G
NC_000010.10:g.89717730A>G
NM_000314.4:c.755A>G
P60484:p.Asp252Gly

Protein change:

D252G; ASP252GLY

Links:

UniProtKB: P60484#VAR_032637; OMIM: 601728.0038; dbSNP: rs121909239

NCBI 1000 Genomes Browser:

rs121909239

Molecular consequence:

NM_000314.8:c.755A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304717.5:c.1274A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304718.2:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PTEN hamartoma tumor syndrome (PHTS)
Synonyms:: PTEN Hamartomatous Tumour Syndrome
Identifiers:: MONDO: MONDO:0017623; MeSH: D006223; MedGen: C1959582

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000886855	Clingen PTEN Variant Curation Expert Panel, Clingen	reviewed by expert panel (ClinGen PTEN ACMG Specifications V3)	Pathogenic (Jun 14, 2023)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 29706633, 21828076, 29706350, 29373119, 25527629 Citation Link,
SCV000946953	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15805158, 21659347, 21828076, 25527629, 26579216, 29785012, 28492532
SCV004847792	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jan 23, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 23335809, 25527629, 21828076, 29706350, 21659347, 29373119, 15805158, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000886855

Clingen PTEN Variant Curation Expert Panel, Clingen

reviewed by expert panel

(ClinGen PTEN ACMG Specifications V3)

Pathogenic
(Jun 14, 2023)

germline

curation

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000946953

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004847792

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Jan 23, 2020)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

A pathogenic role for germline PTEN variants which accumulate into the nucleus.

Mingo J, Rodríguez-Escudero I, Luna S, Fernández-Acero T, Amo L, Jonasson AR, Zori RT, López JI, Molina M, Cid VJ, Pulido R.

Eur J Hum Genet. 2018 Aug;26(8):1180-1187. doi: 10.1038/s41431-018-0155-x. Epub 2018 Apr 30.

PubMed [citation]

PMID:: 29706633
PMCID:: PMC6057996

Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits.

He X, Thacker S, Romigh T, Yu Q, Frazier TW Jr, Eng C.

Mol Autism. 2015;6:63. doi: 10.1186/s13229-015-0056-6. Erratum in: Mol Autism. 2016 Feb 03;7:14. doi: 10.1186/s13229-016-0075-y.

PubMed [citation]

PMID:: 26579216
PMCID:: PMC4647625

See all PubMed Citations (12)

Details of each submission

From Clingen PTEN Variant Curation Expert Panel, Clingen, SCV000886855.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

NM_000314.8(PTEN):c.755A>G (p.Asp252Gly) variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMID: 23335809). PS3_M: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. 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. PP3: REVEL score > 0.7 (score=0.971) PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 23335809).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000946953.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 252 of the PTEN protein (p.Asp252Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features consistent with PTEN hamartoma tumor syndrome (PMID: 15805158, 21659347, 21828076). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7849). 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. Experimental studies have shown that this missense change affects PTEN function (PMID: 25527629, 26579216, 29785012). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847792.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Asp252Gly variant in PTEN has been reported in at least 3 individuals with features of PTEN hamartoma tumor syndrome (Bubien 2013, Pilarski 2011, Butler 2005). This variant was absent from large population studies. It was classified as Likely pathogenic on July 25, 2018 by the ClinGen-approved PTEN Variant Curation expert panel (Variation ID 7849); note, this expert panel also indicated via personal communication that one of the individuals was reportedly a de novo occurrence, though paternityand maternity were not confirmed. In vitro functional studies support an impact on protein function (Spinelli 2015, Rodriguez-Escudero 2011, Fricano-Kugler 2018). PTEN is defined by the PTEN expert Panel as a gene that has low rate of benign missense variation and where missense variants are a common mechanism of disease. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant PTEN hamartoma tumor syndrome. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP2, PS3_Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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