12-112502222-C-T

Position:

chr12-112502222-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP5BS3

This summary comes from the ClinGen Evidence Repository: The c.1678C>T (p.Leu560Phe) variant in PTPN11 (NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe)) has been identified in individuals with some features of a RASopathy but none were diagnosed with a RASopathy (PS4 not met; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data; GTR ID's: 28338, 26957, 21766; SCV000061285.5; SCV000208999.2; SCV000207690.1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data: GTR ID: 26957; SCV000208999.2). In vitro functional studies provide some evidence that the p.Leu560Phe variant does not impact protein function (BS3; PMID:15987685). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied: BS3, BP5 (Version 2.1; 09/17/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA134647/MONDO:0021060/043

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:6B:7

Conservation

PhyloP100: 5.49

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:

PTPN11 (HGNC:):

PTPN11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP5

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

BS3

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5 linkuse as main transcript	c.1678C>T	p.Leu560Phe	missense_variant	14/16	ENST00000351677.7	NP_002825.3	Q06124-2
PTPN11	NM_001330437.2 linkuse as main transcript	c.1690C>T	p.Leu564Phe	missense_variant	14/16		NP_001317366.1	Q06124-1
PTPN11	NM_001374625.1 linkuse as main transcript	c.1675C>T	p.Leu559Phe	missense_variant	14/16		NP_001361554.1
PTPN11	XM_011538613.3 linkuse as main transcript	c.1687C>T	p.Leu563Phe	missense_variant	14/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.1678C>T	p.Leu560Phe	missense_variant	14/16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 linkuse as main transcript	c.1690C>T	p.Leu564Phe	missense_variant	14/15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251088

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.0000353

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1461558

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -

RASopathy

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 560 of the PTPN11 protein (p.Leu560Phe). This variant is present in population databases (rs397516797, gnomAD 0.01%). This missense change has been observed in individual(s) with Noonan syndrome and congenital hypertrophic cardiomyopathy (PMID: 12960218). ClinVar contains an entry for this variant (Variation ID: 44599). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. Experimental studies have shown that this missense change does not substantially affect PTPN11 function (PMID: 15987685). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	The c.1678C>T (p.Leu560Phe) variant in PTPN11 (NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe)) has been identified in individuals with some features of a RASopathy but none were diagnosed with a RASopathy (PS4 not met; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data; GTR ID's: 28338, 26957, 21766; SCV000061285.5; SCV000208999.2; SCV000207690.1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data: GTR ID: 26957; SCV000208999.2). In vitro functional studies provide some evidence that the p.Leu560Phe variant does not impact protein function (BS3; PMID: 15987685). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied: BS3, BP5 (Version 2.1; 09/17/2024). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2019	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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2023	Variant summary: PTPN11 c.1678C>T (p.Leu560Phe) 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 4e-05 in 251088 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in PTPN11 causing Noonan Syndrome (4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.1678C>T has been reported in the literature in at-least one individual affected with Hypertrophic Cardiomyopathy (example, Sarkozy_2003). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on biochemical function (example, Keilhack_2005). Eight clinical diagnostic laboratories including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) and uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2009	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Noonan syndrome and Noonan-related syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Metachondromatosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

PTPN11-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

CardioboostCm

Benign

0.063

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

.;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.21

Sift

Benign

0.12

T;.

Sift4G

Benign

0.60

T;T

Polyphen

0.019

B;.

Vest4

0.69

MutPred

0.70

Loss of glycosylation at P565 (P = 0.2201);.;

MVP

0.79

MPC

0.91

ClinPred

0.094

GERP RS

5.4

Varity_R

0.37

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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