10-87957973-A-G

Position:

• chr10-87957973-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3 PP2 PS4_Supporting PS3_Moderate PM2_Supporting PM6_Strong

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000564/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 8.88

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

PTEN (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.755A>G	p.Asp252Gly	missense_variant	7/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1274A>G	p.Asp425Gly	missense_variant	8/10		NP_001291646.4
PTEN	NM_001304718.2	c.164A>G	p.Asp55Gly	missense_variant	7/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.755A>G	p.Asp252Gly	missense_variant	7/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	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. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 14, 2023	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 23, 2020	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 -

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 29, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25527629, 26579216, 27405757]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15805158, 21194675, 23335809]. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2023

Published functional studies demonstrate a damaging effect: reduced nuclear localization, protein expression, and lipid phosphastase activity, and inability to rescue neuronal hypertrophy in a mouse model (Rodriguez-Escudero et al., 2011; Fricano-Kugler et al., 2018; Spinelli et al., 2015; Mighell et al., 2018; Wong et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29706633, 29706350, 27535533, 26800850, 31086789, 23161105, 27221918, 26053092, 26579216, 17286265, 29373119, 17427195, 27405757, 21659347, 32150788, 23335809, 18626510, 29785012, 25527629, 15805158, 21828076) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The p.D252G pathogenic mutation (also known as c.755A>G), located in coding exon 7 of the PTEN gene, results from an A to G substitution at nucleotide position 755. The aspartic acid at codon 252 is replaced by glycine, an amino acid with similar properties. This mutation was identified in a child with developmental delay and extreme macrocephaly (Butler MG et al. J Med Genet, 2005 Apr;42:318-21) and was found to be de novo in an individual with oral papillomas, facial papules, and extreme macrocephaly (personal communication, Bubien V et al. J Med Genet, 2013 Apr;50:255-63). In one study, D252G demonstrated greater than a 50% reduction in lipid phosphatase activity compared to wild type PTEN (Wong CW et al. FEBS J, 2020 11;287:4848-4861). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). Other assays also support reduced protein expression and/or functional activity compared to wild type (He X et al. Mol Autism, 2015 Nov;6:63; Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955; Mingo J et al. Eur J Hum Genet, 2018 08;26:1180-1187; Post KL et al. Nat Commun, 2020 04;11:2073). Based on structural analysis, this p.D252G is deleterious (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Glioma susceptibility 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 01, 2022

- -

Macrocephaly-autism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.5	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.010	D;D
Polyphen		0.99	D;.
Vest4		0.99
MutPred		0.85		Loss of ubiquitination at K254 (P = 0.0432);.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909239; hg19: chr10-89717730; COSMIC: COSV64296805;