Submissions for variant NM_002834.5(PTPN11):c.1658C>T (p.Thr553Met)

gnomAD frequency: 0.00048  dbSNP: rs148176616

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000033558	SCV000616417	benign	RASopathy	2017-04-03	reviewed by expert panel	curation	The filtering allele frequency of the c.1658C>T (p.Thr553Met) variant in the PTPN11 gene is 0.048% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (49/66556 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Computational prediction tools and conservation analysis suggest that the p.Thr553Met variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP4.
GeneDx	RCV000077855	SCV000057463	benign	not provided	2016-06-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Eurofins Ntd Llc (ga)	RCV000037622	SCV000058287	likely benign	not specified	2013-03-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037622	SCV000061284	likely benign	not specified	2015-03-16	criteria provided, single submitter	clinical testing	p.Thr553Met in exon 14 of PTPN11: This variant has been reported in the literatu re in a fetus with increased nuchal translucency, which is a prenatal feature of Noonan syndrome. However, follow-up clinical information was not provided for t his fetus (Lee 2008). This variant has been identified by our laboratory in 5 in dividuals with clinical features of Noonan syndrome. However, it was also identi fied in 3 parents of unrelated probands in our laboratory who were reportedly un affected (LMM unpublished data). In addition, this variant has been identified i n 49/66556 European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs148176616). Threonine (Thr) at position 553 i s not conserved in mammals or evolutionarily distant species, supporting that a change at this position may be tolerated. Additional computational prediction t ools do not provide strong support for or against an impact to the protein. In s ummary, the p.Thr553Met variant is classified as likely benign based on its pres ence in multiple unaffected individuals and lack of conservation.
Invitae	RCV000033558	SCV000262218	likely benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000077855	SCV000281565	likely benign	not provided	2016-01-18	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Ambry Genetics	RCV000254003	SCV000317878	likely benign	Cardiovascular phenotype	2018-07-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037622	SCV000698060	benign	not specified	2022-02-27	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1658C>T (p.Thr553Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 283484 control chromosomes. The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome And Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is benign. Particularly in an elderly control population, this variant was found at allele frequency of 0.003 (3/1000 chromosomes), strongly supporting for a benign outcome (Beaudoin_2012). c.1658C>T has been reported in the literature including a fetus with clinical features of Noonan syndrome without information of clinical follow-up (Lee_2008), one patient with neurofibromatosis type 1 who also carried an NF1 splice site variant (Sant_2015), three patients with myocardial Infarction (Beaudoin_2012), one patient with breast cancer (Maxwell_2016), one patient with glioblastoma multiforme (Sturla_2011/TCGA database) and one lymphoid neoplasm sample (COSMIC/PMID: 22675565). However, none of the published studies provide strong evidence for or against pathogenicity. This variant has been identified by LMM laboratory in 5 individuals with clinical features of Noonan syndrome. However, it was also identified in 3 parents of unrelated probands who were reportedly unaffected (LMM unpublished data), strongly supporting for benign outcome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submitters and one expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=10). Based on the evidence outlined above, the variant was classified as benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000037622	SCV000740650	likely benign	not specified	2017-05-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000755651	SCV000883050	likely benign	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2022-04-16	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852687	SCV000995396	likely benign	Primary dilated cardiomyopathy; Cardiomyopathy	2018-07-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000988917	SCV001138830	benign	Metachondromatosis	2019-05-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813262	SCV002060590	benign	Noonan syndrome and Noonan-related syndrome	2020-04-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000037622	SCV002068788	likely benign	not specified	2020-11-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000077855	SCV004131974	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PTPN11: PP2, BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV004532498	SCV004751195	likely benign	PTPN11-related disorder	2020-03-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156990	SCV000206713	uncertain significance	Noonan syndrome	2014-01-07	no assertion criteria provided	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000077855	SCV000207689	likely benign	not provided	2015-01-15	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000156990	SCV001438422	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000077855	SCV001799835	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000077855	SCV001951854	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077855	SCV001966764	likely benign	not provided		no assertion criteria provided	clinical testing