chr12-112489080-T-G

Position:

• chr12-112489080-T-G

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_002834.5(PTPN11):​c.1504T>G​(p.Ser502Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S502L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.67

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) in NM_002834.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112489081-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ 3.1293 (greater than the threshold 3.09). Trascript score misZ 4.9438 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 12-112489080-T-G is Pathogenic according to our data. Variant chr12-112489080-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 40556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489080-T-G is described in Lovd as [Pathogenic]. Variant chr12-112489080-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1504T>G	p.Ser502Ala	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1516T>G	p.Ser506Ala	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1501T>G	p.Ser501Ala	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1513T>G	p.Ser505Ala	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1504T>G	p.Ser502Ala	missense_variant	13/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1516T>G	p.Ser506Ala	missense_variant	13/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.517T>G	p.Ser173Ala	missense_variant	5/5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2022	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23832011, 24803665, 15928039, 26242988, 15842656, 16358218, 31263281, 22465605, 18470943) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2020	PS4, PM6_Strong, PM5, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2017	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2021	Variant summary: PTPN11 c.1504T>G (p.Ser502Ala) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Other amino acid changes at this location (Ser502Thr, Ser502Ala, Ser502Leu) have been associated with the clinical features of Noonan syndrome and/or LEOPARD syndrome suggesting that Ser 502 is a critical amino acid essential for protein function (Tartaglia_2006). The variant was absent in 252116 control chromosomes. c.1504T>G has been reported in the literature as a de-novo germline variant in multiple individuals affected with Noonan Syndrome and related disorders as well as a somatic variant in settings of myelodysplastic related acute myeloid leukaemia (example, Kratz_2005, Tartaglia_2005, Tartaglia_2006, Kamisago_2005, Sakaguchi_2013, Ezquieta_2012, Joyce_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 08, 2023	This missense change has been observed in individual(s) with Noonan syndrome and/or PTPN11-related conditions (PMID: 15928039, 26242988). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser502 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12325025, 17020470, 19020799, 32164556). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40556). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 502 of the PTPN11 protein (p.Ser502Ala). -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 07, 2014

The Ser502Ala variant in PTPN11 has been previously identified in 2 individuals with clinical features of Noonan syndrome, including in 1 individual where it wa s found to have occurred de novo and in 1 individual who developed juvenile myel omonocytic leukemia (JMML; Kratz 2005, Sakaguchi 2013). This variant has also be en identified in 1 individual with acute myeloid leukemia (AML; Tartaglia 2005). In addition, this variant is absent from large population studies. Three other amino acid changes at this location (Ser502Thr, Ser502Pro, Ser502Leu) have been associated with the clinical features of Noonan syndrome and/or LEOPARD syndrome , and have also been identified as somatic variants in individuals with hematolo gic malignancies (Tartaglia 2006, Goemans 2005, Paulsson 2007, Ko 2008, Aoki 200 8). In summary, this variant meets our criteria to be classified as pathogenic ( http://pcpgm.partners.org/LMM) based upon de novo occurrence, absence from the g eneral population, and multiple additional pathogenic variants at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostCm	Uncertain	0.80
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.8	D;.;.
REVEL	Pathogenic	0.92
Sift	Benign	0.042	D;.;.
Sift4G	Benign	0.083	T;T;T
Polyphen		0.73	P;.;.
Vest4		0.73
MutPred		0.88		Gain of catalytic residue at S502 (P = 0.0385);.;.;
MVP		0.99
MPC		1.8
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.77

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: rs121918458; hg19: chr12-112926884; COSMIC: COSV61005465; COSMIC: COSV61005465;