ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3839C>T (p.Ala1280Val) (rs74716434)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569836 SCV000672481 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence,Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV000318323 SCV000429928 likely benign Neuroblastoma Susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000540430 SCV000648719 uncertain significance Neuroblastoma 3 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1280 of the ALK protein (p.Ala1280Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs74716434, ExAC 0.01%). This variant has not been reported in the literature in individuals with ALK-related disease. ClinVar contains an entry for this variant (Variation ID: 335691). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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