ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.227A>C (p.Glu76Ala) (rs121918465)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033477 SCV000057382 pathogenic not provided 2016-09-27 criteria provided, single submitter clinical testing The E76A variant has been reported previously as a somatic variation in patients diagnosed with Juvenile Myelomonocytic Leukemia (JMML) without Noonan syndrome (Shimada et al., 2004; Tartaglia et al., 2003). Missense variants in PTPN11 are found in approximately 34% of individuals with JMML without Noonan syndrome. The Glutamic acid 76 residue is an apparent hotspot, with multiple published missense variants (E76K/V/G) associated with JMML (Tartaglia et al., 2003). The E76A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies show that E76A, like other cancer associated variants in PTPN11, confers a greater gain-of-function than variants that are exclusively associated with Noonan syndrome (Kratz et al., 2005; O'Reilly et al., 2000). It is further presumed that the E76A variant is a somatic variant as cancer-associated variants confer a greater gain-of-function than variants exclusively associated with RASopathies and as a consequence are associated with severe prenatal abnormalities and demise. In a paper discussing sequence analysis of the PTPN11 gene in fetuses with ultrasound findings, two fetuses were found to have variants that were predominantly (F71L) or exclusively (T507K) reported in the context of cancer (Lee et al., 2008). Both of these fetuses presented with hydrops fetalis and one of these cases resulted in fetal demise (Lee et al., 2009). The presence of E76A is consistent with the diagnosis of JMML.
OMIM RCV000014267 SCV000034516 pathogenic Juvenile myelomonocytic leukemia 2003-06-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444034 SCV000507249 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424995 SCV000507250 likely pathogenic Neuroblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432192 SCV000507251 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443046 SCV000507252 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424761 SCV000507253 likely pathogenic Astrocytoma 2016-05-31 no assertion criteria provided literature only

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