ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.227A>G (p.Glu76Gly) (rs121918465)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000014266 SCV000204032 pathogenic Juvenile myelomonocytic leukemia 2015-10-18 criteria provided, single submitter clinical testing The p.Glu76Gly variant in PTPN11 has been reported as a somatic change in >10 in dividuals with juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia ( AML), or childhood acute lymphoblastic leukemia (ALL; Tartaglia 2003, Tartaglia 2004, Loh 2004, Kratz 2005). In addition, many other variants at this position h ave been frequently identified as a somatic change in individuals with JMML, AML , and ALL, and codon 76 in PTPN11 has been described as the mutational hot-spot for JMML (Tartaglia 2003). It was absent from large population studies. In summa ry, this variant meets our criteria to be classified as pathogenic for JMML.
GeneDx RCV000159046 SCV000208988 pathogenic not provided 2018-01-22 criteria provided, single submitter clinical testing The E76G pathogenic variant in the PTPN11 gene lies within the region coding for the N-SH2 domain, which is a hot spot for mutations in Noonan syndrome (Tartaglia et al., 2001 and Tartaglia et al., 2006). The E76G is not observed in large population cohorts (Lek et al., 2016). It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Another amino acid substitution at codon 76, E76D, has been reported as germline pathogenic variant in approximately 3% of individuals with Noonan syndrome (Kratz et al., 2005). Other missense variants at the same codon have also been reported as somatic variants in association with juvenile myelomonocytic leukemia (JMML) and other hematologic malignancies (Shimada et al., 2004 and Tartaglia et al., 2006). It has been hypothesized that residues with strong associations to isolated JMML, like this variant, often result in embryonic lethal or severe clinical presentations if inherited as a germline variant (Mason-Suares et al., 2017, Tartaglia et al., 2006; Lee KA et al., 2009, Chan RJ, et al., 2007 Tartaglia M, et al., 2003).
OMIM RCV000014266 SCV000034515 pathogenic Juvenile myelomonocytic leukemia 2003-06-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437931 SCV000507254 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420699 SCV000507255 likely pathogenic Astrocytoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427060 SCV000507256 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437713 SCV000507257 likely pathogenic Neuroblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419574 SCV000507258 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only

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