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 2018-01-13 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000473647 SCV000541534 uncertain significance Hereditary Paraganglioma-Pheochromocytoma Syndromes 2020-10-25 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 2020-02-27 criteria provided, single submitter clinical testing The p.V9L variant (also known as c.25G>T), located in coding exon 1 of the MAX gene, results from a G to T substitution at nucleotide position 25. The valine at codon 9 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in 1 of 1694 patients with pheochromocytoma or paraganglioma; this patient was a 13 year old male with a pheochromocytoma and a thoracoabdominal paraganglioma (Burnichon N et al. Clin. Cancer Res. 2012 May; 18(10):2828-37; Comino-Méndez I et al. J. Mol. Med. 2015 Nov; 93(11):1247-55). Additionally, in a Luciferase reporter assay, the alteration MAX p.V9L was found to have a minor impact on MYC’s E-box transcriptional activation (Comino-Méndez I et al. J. Mol. Med. 2015 Nov; 93(11):1247-55). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics,Fulgent Genetics RCV000351964 SCV000894877 uncertain significance Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing

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