ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.4375G>T (p.Ala1459Ser) (rs372612147)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000555867 SCV000429919 likely benign Neuroblastoma 3 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000555867 SCV000648743 uncertain significance Neuroblastoma 3 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1459 of the ALK protein (p.Ala1459Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs372612147, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with ALK-related disease. ClinVar contains an entry for this variant (Variation ID: 335689). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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