ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3595A>T (p.Met1199Leu)

gnomAD frequency: 0.00002  dbSNP: rs1400239417
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000689780 SCV000817447 uncertain significance Neuroblastoma, susceptibility to, 3 2023-12-04 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1199 of the ALK protein (p.Met1199Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with medulloblastoma (PMID: 27179218). ClinVar contains an entry for this variant (Variation ID: 569205). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Baylor Genetics RCV000689780 SCV001482607 uncertain significance Neuroblastoma, susceptibility to, 3 2019-05-09 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics RCV002334275 SCV002619441 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-07 criteria provided, single submitter clinical testing The p.M1199L variant (also known as c.3595A>T), located in coding exon 23 of the ALK gene, results from an A to T substitution at nucleotide position 3595. The methionine at codon 1199 is replaced by leucine, an amino acid with highly similar properties. This variant has been reported in the germline of an individual with medulloblastoma and was inherited from an unaffected parent (Trubicka J et al. Folia Neuropathol, 2016;54:23-30). 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.

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