ClinVar Miner

Submissions for variant NM_002382.5(MAX):c.25G>T (p.Val9Leu) (rs201743423)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000351964 SCV000387944 uncertain significance Pheochromocytoma 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000473647 SCV000541534 uncertain significance Hereditary Paraganglioma-Pheochromocytoma Syndromes 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 9 of the MAX protein (p.Val9Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs201743423, ExAC 0.1%). This variant has been reported in an individual affected with adrenal pheochromocytoma and thoracoabdominal paraganglioma (PMID: 22452945). ClinVar contains an entry for this variant (Variation ID: 313819). An experimental study has shown that this missense change affects the transcriptional repression activity of the MAX protein in vitro (PMID: 26070438). However, no effect was detected in the presence of wild-type protein, suggesting this variant does not act in a dominant-negative manner (PMID: 26070438). 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.
GeneDx RCV000488919 SCV000576683 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing This variant is denoted MAX c.25G>T at the cDNA level, p.Val9Leu (V9L) at the protein level, and results in the change of a Valine to a Leucine (GTG>TTG). This variant was has been reported in one individual with bilateral pheochromocytoma and in another individual with both a pheochromocytoma and paraganglioma (Burnichon 2012, Menara 2015). However, loss of heterozygosity (LOH) was not detected in the tumor of one of the individuals for which LOH was performed (Burnichon 2012). A luciferase reporter assay showed that this variant is unable to fully repress MYC activity compared to wildtype (Comino-Mendex 2015). MAX Val9Leu was observed at an allele frequency of 0.05% in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MAX Val9Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569331 SCV000673604 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000351964 SCV000894877 uncertain significance Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing

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