rs121909222

Positions:

• chr10-87933127-A-G
• chr10-87933127-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM6 PP2 PM1 PS3

This summary comes from the ClinGen Evidence Repository: PTEN c.368A>G (p.His123Arg) 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).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 10234502)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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000418/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• 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 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.368A>G	p.His123Arg	missense_variant	5/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.887A>G	p.His296Arg	missense_variant	6/10		NP_001291646.4
PTEN	NM_001304718.2	c.-383A>G		5_prime_UTR_variant	4/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.368A>G	p.His123Arg	missense_variant	5/9	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:6

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 18, 2020	PTEN c.368A>G (p.His123Arg) 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). PS3: Phosphatase activity <50% of wild type (PMID 29706350) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 10234502) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His123 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9256433, 10555148, 10772829, 16619501, 21828076; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350). 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: 7816). This missense change has been observed in individuals with clinical features of PTEN-related conditions (PMID: 9259288, 10234502; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 123 of the PTEN protein (p.His123Arg). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2017	This variant is denoted PTEN c.368A>G at the cDNA level, p.His123Arg (H123R) at the protein level,and results in the change of a Histidine to an Arginine (CAC>CGC). This variant was found to occur de novo in apatient with Cowden syndrome (Nelen 1997, Nelen 1999). Additionally, other amino acid changes at the His123residue - PTEN His123Gln, His123Tyr, and His123Asp - have been reported in individuals with clinical historiesconsistent with PTEN Hamartoma Tumor syndrome and on functional interrogation demonstrated absent or decreasedphosphatase activity and inability to rescue or regulate cell growth (Myers 1997, Lee 1999, Bussaglia 2002, Rodriguez-Escudero 2011, Kersseboom 2011, Spinelli 2015, Hansen-Kiss 2017). PTEN His123Arg was not observed in largepopulation cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). SinceHistidine and Arginine share similar properties, this is considered a conservative amino acid substitution. PTENHis123Arg occurs at a position that is conserved across species and is located in an ATP binding motif andphosphatase core domain (Lee 1999, Lobo 2009, Molinari 2014). In silico analyses predict that this variant is probablydamaging to protein structure and function. Based on currently available evidence, we consider this variant to bepathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 15, 2021	This variant has been reported in the published literature in an individual affected with Cowden syndrome and a malignancy in the thyroid gland (PMID: 9259288 (1997), 10234502 (1999)). In addition, a functional study using transformed yeast and analysis by logistic regression has described the variant as having reduced PTEN activity to truncation-like levels (PMID: 29706350 (2018), 32442409 (2020)). Based on the available information, this variant is classified as pathogenic. -

PTEN-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2023

The PTEN c.368A>G variant is predicted to result in the amino acid substitution p.His123Arg. This variant was reported in individuals with PTEN hamartoma tumor syndrome, including at least one de novo case (patient n40, Nelen et al. 1999. PubMed ID: 10234502; Wang et al. 2023. PubMed ID: 36453251). Functional studies showed that this variant impacts protein function (Table S1, Mighell et al. 2020. PubMed ID: 32442409). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.His123Asp and p.His123Tyr) have been reported in individuals with PTEN hamartoma tumor syndrome (Human Gene Mutation Database). The c.368A>G (p.His123Arg) variant is classified as pathogenic by ClinGen PTEN Variant Curation Expert Panel. This variant is interpreted as pathogenic. -

Cowden syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Gain of MoRF binding (P = 0.0376);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121909222; hg19: chr10-89692884; COSMIC: COSV64309701;