chr10-87933129-T-C

Variant names:

• chr10-87933129-T-C
• rs121909223
• NM_000314.8:c.370T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP2 PM6_Strong PS4_Supporting PM1 PS3 PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.370T>C (p.Cys124Arg) 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 10866302, PMID 29706350)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor SCV000568254.4)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).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.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000568254.4) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000422/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.62
• Publications: 36 publications found

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 Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 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.
• 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 rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.370T>C	p.Cys124Arg	missense_variant	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.889T>C	p.Cys297Arg	missense_variant	Exon 6 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-381T>C		5_prime_UTR_variant	Exon 4 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.370T>C	p.Cys124Arg	missense_variant	Exon 5 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

Aug 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 27, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9467011]. Functional studies indicate this variant impacts protein function [PMID: 17324556, 20685300, 10866302]. -

PTEN hamartoma tumor syndrome Pathogenic:2

Jun 25, 2019

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.370T>C (p.Cys124Arg) 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 10866302, PMID 29706350) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor SCV000568254.4) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations (PMID 27535533). 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000568254.4) -

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 124 of the PTEN protein (p.Cys124Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Cowden syndrome or Cowden syndrome-like (PMID: 9259288, 9467011, 9832031, 21194675). ClinVar contains an entry for this variant (Variation ID: 7817). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302, 20194734). This variant disrupts the p.Cys124 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10555148, 17324556, 21828076, 22962422, 25647146). 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. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Aug 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: loss of phosphatase activity, protein instability, and mouse model recapitulating human tumor phenotypes (PMID: 10866302, 29706350, 29785012, 20194734); 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: 25448479, 19734154, 10555148, 10866302, 20194734, 24292679, 21888769, 12938083, 9259288, 9600246, 9467011, 12560928, 26800850, 15987703, 23161105, 9847190, 16506206, 12789288, 10923032, 19400696, 19457929, 24475377, 29706350, 29785012, 23335809, 10234502, 36243179) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 15, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C124R pathogenic variant (also known as c.370T>C), located in coding exon 5 of the PTEN gene, results from a T to C substitution at nucleotide position 370. The cysteine at codon 124 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration occurs in a catalytically active residue responsible for dephosphorylating the phospholipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is critical for tumor suppressor function (Xiao Y et al. Cell. Signal. 2007 Jul; 19(7):1434-45; Chia JY et al. Biochim. Biophys. Acta. 2010 Sep; 1804(9):1785-95). This alteration was reported in a patient with macrocephaly, thyroid adenoma, and skin findings (Nelen MR et al. Hum. Mol. Genet., 1997 Aug;6:1383-7). It has also been detected in patients meeting clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43; Ambry internal data). Functional studies have shown that this alteration leads to complete loss of phosphatase activity (Han S et al. Cancer Res. 2000 Jun;60(12):3147-51). In another study using mouse models, heterozygous PTEN p.C124R knockin mice showed cancer predisposition similar to Cowden syndrome with nearly undetectable PTEN protein expression and PTEN p.C124R homozygous mice exhibited abnormal embroyonic development as well as lethality (Wang H et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Mar;107(11):5142-7). Another variant at the same amino acid position, p.C124S, has been reported as likely pathogenic based on identification in multiple individuals with Cowden syndrome/Cowden-like syndrome and functional analysis demonstrated loss of PTEN phosphatase activity (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Rodr&iacute;guez-Escudero I et al. Hum. Mol. Genet. 2011 Nov;20:4132-42; He X et al. J. Clin. Endocrinol. Metab. 2012 Nov;97:E2179-87; Myers MP et al. Proc. Natl. Acad. Sci. U.S.A., 1998 Nov;95:13513-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Gain of disorder (P = 0.003);
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909223; hg19: chr10-89692886; COSMIC: COSV64294667;