rs121913294

chr10-87952143-G-Achr10-87952143-G-Cchr10-87952143-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):c.518G>A(p.Arg173His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87952142-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 189500.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 10-87952143-G-A is Pathogenic according to our data. Variant chr10-87952143-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87952143-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-87952143-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.518G>A	p.Arg173His	missense_variant	6/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1037G>A	p.Arg346His	missense_variant	7/10
PTEN	NM_001304718.2	c.-74G>A		5_prime_UTR_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.518G>A	p.Arg173His	missense_variant	6/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251148 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135744

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461138 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000104 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han et al., 2000; Rodriguez-Escudero et al., 2011; Mighell et al., 2018); 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: 21828076, 25527629, 23335809, 30720243, 29625052, 24721394, 20533527, 23161105, 28526761, 17526800, 21659347, 26800850, 28201779, 28304377, 28984400, 16506206, 11875759, 20718038, 18986487, 29706350, 19265751, 24475377, 33482836, 36192478, 10866302) -

PTEN hamartoma tumor syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a heterozygous change in patients with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 23335809, 20533527, 28526761). In vitro assays showed that this variant is associated with decreased phosphatase activity (PMID: 21828076, 10866302). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001 % (2/251148) and thus is presumed to be rare. The c.518G>A (p.Arg173His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.518G>A (p.Arg173His) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 173 of the PTEN protein (p.Arg173His). This variant is present in population databases (rs121913294, gnomAD 0.01%). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 20533527, 23335809; Invitae). ClinVar contains an entry for this variant (Variation ID: 376032). 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: 10866302). This variant disrupts the p.Arg173 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10866302, 17526800, 25669429, 28475857). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Herman Laboratory, Nationwide Children's Hospital	Mar 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 20, 2016	The p.Arg173His variant has been reported in 4 individuals with clinical feature s of Cowden syndrome (Lachlan 2007, Mcbride 2010, Bubien 2013) and segregated wi th disease in 2 affected relatives from 2 different families (Lachlan 2007, Varg a 2004). In addition, it segregated with macrocephaly in 1 relative from a third family (McBride 2010). This variant has been identified in 1/10324 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913294). This variant has been observed as a somatic mutation in t umors, including glioblastoma (Duerr 1998) and colorectal cancer (Day 2013). The p.Arg173His variant is associated with decreased protein activity in vitro (Han 2000, Rodriguez-Escudero 2011). However, these types of assays may not accurate ly represent biological function. In summary, although additional studies are re quired to fully establish its clinical significance, the p.Arg173His variant is likely pathogenic in an autosomal dominant manner. -

Cowden syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R173H in PTEN (NM_000314.8) has been reported before both in a patient with developmental delay (Varga EA et al) as well as in patients with PTEN related hamartoma syndrome (Bubien et al; Hansen et al).Functional studies revealed reduced phosphatse activity (Rodriguez-Escudero et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. The p.R173H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 173 of PTEN is conserved in all mammalian species. The nucleotide c.518 in PTEN is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 28, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17526800, 18626099, 19265751, 20533527, 23335809]. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 17, 2021	- -

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2023

The p.R173H variant (also known as c.518G>A), located in coding exon 6 of the PTEN gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with clinical features of PTEN-hamartoma tumor syndrome (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Varga EA et al. Genet. Med., 2009 Feb;11:111-7; McBride KL et al. Autism Res, 2010 Jun;3:137-41; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; van der Velden JJ. et al. Int. J. Dermatol. 2008 Nov;47 Suppl 1:45-8). In one study, functional assays demonstrated that this alteration inactivates phosphastase activity (Han SY et al. Cancer Res., 2000 Jun;60:3147-51); however, in vivo yeast assays demonstrated partial phosphastase activity in another study (Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). Another study determined that p.R173H has an intermediate effect on regulating p53 and Gata3 levels compared to wild-type and nonsense alleles (Xu J et al. Transl Oncol, 2014 Apr;7:196-205.e1). This amino acid position is highly conserved in available vertebrate species. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Loss of stability (P = 0.0435);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.98

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: rs121913294; hg19: chr10-89711900; COSMIC: COSV64288961; COSMIC: COSV64288961;