rs751437780

chr12-112450353-A-Gchr12-112450353-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PM5 PP2 PP5 BS2

The NM_002834.5(PTPN11):c.173A>G(p.Asn58Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,613,116 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N58D) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7
• Conservation: PhyloP100: 9.31

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 2 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002834.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112450352-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PTPN11
• PP5: Variant 12-112450353-A-G is Pathogenic according to our data. Variant chr12-112450353-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372483.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2}.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.173A>G	p.Asn58Ser	missense_variant	3/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.173A>G	p.Asn58Ser	missense_variant	3/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 251000 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000794

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000671 AC: 98 AN: 1460942 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 726830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000819

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PTPN11: PM1, PM5, PP3, PP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2023	Observed as a somatic variant in a lung cancer cell line (Bentires-Alj et al., 2004) and as a germline variant in an individual with childhood acute lymphoblastic leukemia (Case et al., 2008); 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: 25695693, 26214590, 15604238, 18701506, 23825065, 23957426, 24480804, 20579941, 27168466, 30050098, 11992261, 9491886, 16053901, 29493581, 35385746, 29625052, 29907801) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PTPN11 p.Asn58Ser variant was identified in dbSNP (ID: rs751437780), ClinVar (classified as a VUS by Invitae, GeneDx and Integrated Genetics/Laboratory Corporation of America) and Cosmic (FATHMM prediction of pathogenic; score=0.99). The variant was also identified in control databases in 10 of 282404 chromosomes at a frequency of 0.000035 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 10 of 128726 chromosomes (freq: 0.000078), but not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The N58S variant has been identified somatically in a metastatic breast tumor (Goswami_2015_PMID:25695693). Germline mutations at the same residue (N58H, N58D and N58K) have been identified in patients with Noonan syndrome and LEOPARD syndrome, and the N58Y somatic mutation was identified in patients with hematologic malignancies (Coromilas_2015_PMID:25914815; Tartaglia_2006_PMID:16358218). The p.Asn58 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 02, 2018	Variant summary: PTPN11 c.173A>G (p.Asn58Ser) results in a conservative amino acid change located in the first SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.26 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.173A>G in individuals affected with Noonan Syndrome and Related Conditions has been reported. However, c.173A>G (p.Asn58Ser) has been observed previously as a somatic mutation in a lung cancer cell line (Bentires-Alj 2004) and was reported in association with childhood acute lymphoblastic leukemia in an individual as a somatic and germline variant (Case 2008). Other missense variants affecting the same amino acid position have been reported in Noonan syndrome (N58K, N58D, N58K; Kratz 2005, Tartaglia 2006) and childhood acute leukemia (N58Y, somatic, Tartaglia 2004); these reports might indicate the importance of this residue for protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. The c.173A>G has been identified in an internal sample undergoing genetic testing due to abnormal US findings and was confirmed to be is maternally inherited. However, mother was not evaluated by clinical geneticist and, therefore association of N58S with NS remains to be established (internal data). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 22, 2019	- -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 58 of the PTPN11 protein (p.Asn58Ser). This variant is present in population databases (rs751437780, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of PTPN11-related conditions (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 372483). 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 with a positive predictive value of 95%. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15956085, 16263833, 16804314, 19125092, 25914815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2019

The p.N58S variant (also known as c.173A>G), located in coding exon 3 of the PTPN11 gene, results from an A to G substitution at nucleotide position 173. The asparagine at codon 58 is replaced by serine, an amino acid with highly similar properties. Alternate amino acid substitutions at this position, p.N58H, p.N58D, and p.N58K, have been reported in individuals with Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
CardioboostCm	Benign	0.039
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.96	L;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.5	D;D;.;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.020	D;D;.;.
Sift4G	Benign	0.12	T;T;.;T
Polyphen		0.97	D;P;.;.
Vest4		0.90
MVP		0.86
MPC		1.6
ClinPred		0.54	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.58

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: rs751437780; hg19: chr12-112888157; COSMIC: COSV61005707; COSMIC: COSV61005707;