12-112450361-G-T

Position:

• chr12-112450361-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The ENST00000351677.7(PTPN11):​c.181G>T​(p.Asp61Tyr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D61A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 ENST00000351677.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.99

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000351677.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112450362-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.947
• PP5: Variant 12-112450361-G-T is Pathogenic according to our data. Variant chr12-112450361-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228392.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1}. Variant chr12-112450361-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.181G>T	p.Asp61Tyr	missense_variant	3/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.181G>T	p.Asp61Tyr	missense_variant	3/16	1	NM_002834.5	ENSP00000340944	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 28, 2021	PP2, PP3, PM1, PM2, PM5, PS3, PS4 -

Noonan syndrome 1 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Sep 09, 2024	The reported PTPN11 mutation is somatic. PTPN11 is one of the most commonly altered genes in juvenile myelomonocytic leukemia (JMML) and its presence strongly supports a diagnosis of JMML. The PTPN11D61Y is possible germline mutation . -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 06, 2015

The p.Asp61Tyr in PTPN11 has been previously reported as a somatic variant in at least 30 sporadic cases of JMML, 10 sporadic cases of other hematological malig nancies, and 1 child with neuroblastoma (Tartaglia 2003, Loh 2004, Tartaglia 200 4, Bentires-Alj 2004, Kratz 2005, Tartaglia 2006, Gelsi-Boyer 2008, Paulsson 200 8, Silva 2009, Yoshida 2009, Pugh 2013, Sakaguchi 2013, Strullu 2014) and was ab sent from large population studies. In vitro and in-vivo studies using mouse mod els have shown strong evidence that this variant affects the protein (Tarataglia 2003, Loh 2004, Chan 2005, Chan 2009, Yang 2010). Other variants at this positi on (p.Asp61Gly, p.Asp61Ala, p.Asp61Asn, p.Asp61His, p.Asp61Val) were also report ed in multiple patients with Noonan syndrome and/or hematological malignancies ( Tartaglia 2005, Kratz 2005, Bertola 2006, Sakaguchi 2013, Strullu 2014). In summ ary, this variant meets our criteria to be classified as pathogenic for JMML (ww w.partners.org/personalizedmedicine/lmm). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.81
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.4	D;D;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.98
MutPred		0.82		Loss of phosphorylation at Y63 (P = 0.0746);Loss of phosphorylation at Y63 (P = 0.0746);Loss of phosphorylation at Y63 (P = 0.0746);Loss of phosphorylation at Y63 (P = 0.0746);
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.84

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: rs397507510; hg19: chr12-112888165; COSMIC: COSV61004841; COSMIC: COSV61004841;