Submissions for variant NM_002834.5(PTPN11):c.255C>T (p.His85=)

gnomAD frequency: 0.02271  dbSNP: rs61736914

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000149837	SCV000616443	benign	RASopathy	2017-04-18	reviewed by expert panel	curation	The filtering allele frequency of the c.255C>T (p.His85=) variant in the PTPN11 gene is 7.417% (818/10402) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
Eurofins Ntd Llc (ga)	RCV000037642	SCV000058292	benign	not specified	2013-03-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037642	SCV000061304	benign	not specified	2015-01-08	criteria provided, single submitter	clinical testing	p.His85His in exon 3 of PTPN11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 7.8% (830/10580) o f African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs61736914).
GeneDx	RCV000037642	SCV000171231	benign	not specified	2012-01-17	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001723590	SCV000206754	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037642	SCV000309206	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000250837	SCV000318295	benign	Cardiovascular phenotype	2015-09-17	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV000356750	SCV000376320	benign	Metachondromatosis	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000273664	SCV000376321	benign	LEOPARD syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001094232	SCV000376322	benign	Noonan syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000149837	SCV000560642	benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813212	SCV002060591	benign	Noonan syndrome and Noonan-related syndrome	2021-02-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315517	SCV004017220	benign	Juvenile myelomonocytic leukemia	2023-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030387	SCV000053056	benign	Noonan syndrome	2011-10-26	no assertion criteria provided	clinical testing
Baylor Genetics	RCV000149837	SCV000196681	benign	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000037642	SCV000207664	benign	not specified	2015-01-15	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037642	SCV001917424	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723590	SCV001956389	likely benign	not provided		no assertion criteria provided	clinical testing