Submissions for variant NM_002834.5(PTPN11):c.173A>G (p.Asn58Ser)

gnomAD frequency: 0.00004  dbSNP: rs751437780

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413828	SCV000490755	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691488	SCV000819269	uncertain significance	RASopathy	2024-12-30	criteria provided, single submitter	clinical testing	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, 33850299). ClinVar contains an entry for this variant (Variation ID: 372483). Invitae Evidence 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 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. 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780655	SCV000918108	uncertain significance	not specified	2018-04-02	criteria provided, single submitter	clinical testing	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.
Genetic Services Laboratory, University of Chicago	RCV000780655	SCV002068571	uncertain significance	not specified	2019-02-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411277	SCV002715170	uncertain significance	Cardiovascular phenotype	2024-08-12	criteria provided, single submitter	clinical testing	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. This variant has been detected in a case with thickened nuchal fold, and in somatic and germline samples from individuals with cancer diagnoses; however, Noonan syndrome features were not described (Bentires-Alj M et al. Cancer Res, 2004 Dec;64:8816-20; Case M et al. Cancer Res, 2008 Aug;68:6803-9; Radtke I et al. Proc Natl Acad Sci U S A, 2009 Aug;106:12944-9; Ryan SL et al. Leukemia, 2016 Sep;30:1824-31; Huang KL et al. Cell, 2018 Apr;173:355-370.e14; Leach NT et al. Genet Med, 2019 Feb;21:417-425; Singhal D et al. Leukemia, 2021 Nov;35:3245-3256; Junk SV et al. Leukemia, 2024 Apr;38:887-892). Another variant at the same codon, p.N58D (c.172A>G), has been reported in association 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.
CeGaT Center for Human Genetics Tuebingen	RCV000413828	SCV004700976	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PTPN11: PM1, PM5, PP3, PP4
Fulgent Genetics, Fulgent Genetics	RCV005010309	SCV005632271	uncertain significance	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2024-03-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000413828	SCV001551408	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000413828	SCV002034178	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000413828	SCV002035009	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735501	SCV005360174	uncertain significance	PTPN11-related disorder	2024-05-01	no assertion criteria provided	clinical testing	The PTPN11 c.173A>G variant is predicted to result in the amino acid substitution p.Asn58Ser. This variant has been reported in a fetus with increased nuchal translucency (Table S2, Leach et al. 2019. PubMed ID: 29907801). In ClinVar, this variant has conflicting interpretations of pathogenicity of uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/372483/). However, this variant has also been reported in 10 out of ~282,000 alleles in the gnomAD v2 database (as displayed in the table above). In addition, in gnomAD v4 (available only on GRCh38), this variant is reported in 103 out of ~1,613,000 alleles (https://gnomad.broadinstitute.org/variant/12-112450353-A-G?dataset=gnomad_r4). Alternate missense variants affecting this amino acid (p.Asn58His, p.Asn58Asp, p.Asn58Lys) have been reported as pathogenic (ClinVar IDs: 40486, 40487, 40488, 40489). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.