12-112502202-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1658C>T (p.Thr553Met) variant in the PTPN11 gene (NM_002834.5(PTPN11):c.1658C>T (p.Thr553Met)) is 0.048% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (49/66556 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Computational prediction tools and conservation analysis suggest that the p.Thr553Met variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied: BA1, BP4 (Version 2.1; 09/17/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA134644/MONDO:0021060/043

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 1 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:21

Conservation

PhyloP100: 2.73

Variant links:

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

PTPN11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.1658C>T	p.Thr553Met	missense_variant	Exon 14 of 16	ENST00000351677.7	NP_002825.3	Q06124-2
PTPN11	NM_001330437.2 link	c.1670C>T	p.Thr557Met	missense_variant	Exon 14 of 16		NP_001317366.1	Q06124-1
PTPN11	NM_001374625.1 link	c.1655C>T	p.Thr552Met	missense_variant	Exon 14 of 16		NP_001361554.1
PTPN11	XM_011538613.3 link	c.1667C>T	p.Thr556Met	missense_variant	Exon 14 of 16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.1658C>T	p.Thr553Met	missense_variant	Exon 14 of 16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.1670C>T	p.Thr557Met	missense_variant	Exon 14 of 15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000446

AC:

112

AN:

251054

Hom.:

AF XY:

0.000420

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000688

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000919

AC:

1343

AN:

1461628

Hom.:

Cov.:

AF XY:

0.000884

AC XY:

643

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000440

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000407

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:21

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:8

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTPN11: BP4, BS1 -

Jan 18, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:5

Mar 01, 2013

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PTPN11 c.1658C>T (p.Thr553Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 283484 control chromosomes. The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome And Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is benign. Particularly in an elderly control population, this variant was found at allele frequency of 0.003 (3/1000 chromosomes), strongly supporting for a benign outcome (Beaudoin_2012). c.1658C>T has been reported in the literature including a fetus with clinical features of Noonan syndrome without information of clinical follow-up (Lee_2008), one patient with neurofibromatosis type 1 who also carried an NF1 splice site variant (Sant_2015), three patients with myocardial Infarction (Beaudoin_2012), one patient with breast cancer (Maxwell_2016), one patient with glioblastoma multiforme (Sturla_2011/TCGA database) and one lymphoid neoplasm sample (COSMIC/PMID: 22675565). However, none of the published studies provide strong evidence for or against pathogenicity. This variant has been identified by LMM laboratory in 5 individuals with clinical features of Noonan syndrome. However, it was also identified in 3 parents of unrelated probands who were reportedly unaffected (LMM unpublished data), strongly supporting for benign outcome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submitters and one expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=10). Based on the evidence outlined above, the variant was classified as benign. -

Nov 30, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr553Met in exon 14 of PTPN11: This variant has been reported in the literatu re in a fetus with increased nuchal translucency, which is a prenatal feature of Noonan syndrome. However, follow-up clinical information was not provided for t his fetus (Lee 2008). This variant has been identified by our laboratory in 5 in dividuals with clinical features of Noonan syndrome. However, it was also identi fied in 3 parents of unrelated probands in our laboratory who were reportedly un affected (LMM unpublished data). In addition, this variant has been identified i n 49/66556 European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs148176616). Threonine (Thr) at position 553 i s not conserved in mammals or evolutionarily distant species, supporting that a change at this position may be tolerated. Additional computational prediction t ools do not provide strong support for or against an impact to the protein. In s ummary, the p.Thr553Met variant is classified as likely benign based on its pres ence in multiple unaffected individuals and lack of conservation. -

May 15, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome

Uncertain:2

Jan 07, 2014

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy

Benign:2

Sep 17, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The filtering allele frequency of the c.1658C>T (p.Thr553Met) variant in the PTPN11 gene (NM_002834.5(PTPN11):c.1658C>T (p.Thr553Met)) is 0.048% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (49/66556 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Computational prediction tools and conservation analysis suggest that the p.Thr553Met variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied: BA1, BP4 (Version 2.1; 09/17/2024). -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metachondromatosis

Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Jul 13, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTPN11-related disorder

Benign:1

Mar 30, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Jul 27, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1

Benign:1

Apr 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Benign:1

Apr 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

CardioboostCm

Benign

0.0050

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.91

N;.

REVEL

Benign

0.14

Sift

Benign

0.25

T;.

Sift4G

Benign

0.16

T;T

Polyphen

0.94

P;.

Vest4

0.31

MVP

0.66

MPC

1.5

ClinPred

0.021

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.080

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over