Submissions for variant NM_002834.5(PTPN11):c.226G>A (p.Glu76Lys)

dbSNP: rs121918464

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212892	SCV000057381	pathogenic	not provided	2021-06-03	criteria provided, single submitter	clinical testing	Reported in published literature in patients with juvenile myelomonocytic leukemia (Kratz et al., 2005); Reported in published literature in association with somatic hematologic malignancies (Tartaglia et al., 2006); Published functional studies demonstrate a damaging effect on protein function and structure (Tartaglia et al., 2006; Gagne-Sansfaon et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22391158, 17177198, 29206716, 27582544, 15928039, 16358218, 9491886, 16053901, 11992261, 29493581, 27535533, 27783593, 23825065, 31222725, 15842656, 15385933, 14982869, 32697817, 12717436, 21930766, 19047918, 18470943, 14644997)
Blueprint Genetics	RCV000212892	SCV000927623	pathogenic	not provided	2018-04-09	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000014264	SCV001365520	pathogenic	Juvenile myelomonocytic leukemia	2019-06-21	criteria provided, single submitter	clinical testing	The p.Glu76Lys variant in PTPN11 is an established pathogenic variant that has been identified as a somatic change in >40 individuals with JMML (Tartaglia 2003, Loh 2004, Kratz 2005, Tartaglia 2005, Aoki 2008, Yoshida 2009) and is absent from large population studies. In vitro and in vivo functional studies show that this variant has a strong gain of function impact (Tartaglia 2003, Loh 2004, Xu 2011, Yu 2013, Chang 2016, Dong 2016). Several other variants involving this codon have been identified in individuals with Noonan syndrome and/or hematological malignancies. In summary, this variant meets criteria to be classified as pathogenic for JMML.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000033476	SCV001535902	uncertain significance	RASopathy	2024-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 76 of the PTPN11 protein (p.Glu76Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (JMML) (PMID: 12717436, 14644997, 14982869). ClinVar contains an entry for this variant (Variation ID: 13336). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 14974085, 19509418). This variant disrupts the p.Glu76 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 12634870, 16830086, 18678287). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000212892	SCV003917245	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	PTPN11: PM1, PM2, PM5, PP2, PP3, PS3:Supporting, PS4:Supporting
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004545728	SCV004046253	pathogenic	PTPN11-related disorder		criteria provided, single submitter	clinical testing	This variant has not been previously reported as a germline variant to our knowledge; however, it has been observed as a somatic variant in individuals with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (PMID:14644997, 14982869, 12717436). This variant is in the N-SH2 domain, which is a hotspot domain for pathogenic variants associated with PTPN11 - related disorders. Different amino acid changes at the same residue (p.Glu76Asp, p.Glu76Gln, p.Glu76Gly, p.Glu76Val) have been previously reported in individuals with Noonan syndrome and/or hematological malignancies (PMID: 16830086, 11704759, 18678287, 12634870). Functional studies showed that the c.226G>A (p.Glu76Lys) variant has a gain-of-function effect on the PTPN11 protein (PMID: 14974085, 19509418, 27783593). It is absent from the gnomAD population database and thus is presumed to be rare. The c.226G>A (p.Glu76Lys) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.226G>A (p.Glu76Lys) variant is classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004813039	SCV005438520	pathogenic	Noonan syndrome 1	2024-12-18	criteria provided, single submitter	clinical testing
OMIM	RCV000014264	SCV000034513	pathogenic	Juvenile myelomonocytic leukemia	2003-06-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000033476	SCV000196661	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156974	SCV000206696	pathogenic	Noonan syndrome	2013-05-10	no assertion criteria provided	clinical testing
Investigational Cancer Therapeutics, MD Anderson Cancer Center	RCV001254876	SCV001424769	uncertain significance	Malignant neoplastic disease		no assertion criteria provided	research