12-112472969-T-G

Position:

• chr12-112472969-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PM1

This summary comes from the ClinGen Evidence Repository: The c.782T>G (p.Leu261Arg) variant in PTPN11 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in several individuals whose features appear suggestive of a RASopathy; however, none were sufficiently phenotyped or received clinical diagnoses of a RASopathy (PS4 not met). This variant occurs in a region defined by the ClinGen RASopathy Expert Panel as a mutational hotspot of PTPN11 (PM1; PMID:29493581). Additionally, the Expert Panel has defined PTPN11 as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, the clinical significance of this variant is uncertain based on RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM1, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603294/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 3.97

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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
PTPN11	NM_002834.5	c.782T>G	p.Leu261Arg	missense_variant	7/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.782T>G	p.Leu261Arg	missense_variant	7/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.782T>G	p.Leu261Arg	missense_variant	7/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 29, 2022	Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p. Leu261 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22465605, 28074573). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 280939). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 261 of the PTPN11 protein (p.Leu261Arg). -
Uncertain significance, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Mar 16, 2020	The c.782T>G (p.Leu261Arg) variant in PTPN11 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in several individuals whose features appear suggestive of a RASopathy; however, none were sufficiently phenotyped or received clinical diagnoses of a RASopathy (PS4 not met). This variant occurs in a region defined by the ClinGen RASopathy Expert Panel as a mutational hotspot of PTPN11 (PM1; PMID: 29493581). Additionally, the Expert Panel has defined PTPN11 as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of this variant is uncertain based on RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM1, PM2, PP2. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2024

Identified in patients with Noonan spectrum disorders referred for genetic testing at GeneDx and in published literature (PMID: 38572385); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 11992261, 9491886, 16053901, 29493581, 38572385) -

Neurofibromatosis-Noonan syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
CardioboostCm	Uncertain	0.32
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;T
Eigen	Benign	0.040
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.63	N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.47	N;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.61	T;T;.
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0070	B;B;.
Vest4		0.81
MutPred		0.38		Gain of MoRF binding (P = 0.0149);Gain of MoRF binding (P = 0.0149);Gain of MoRF binding (P = 0.0149);
MVP		0.98
MPC		2.0
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.66

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

Other links and lift over

dbSNP: rs765642157; hg19: chr12-112910773;