Submissions for variant NM_004304.5(ALK):c.3599C>T (p.Ala1200Val)

gnomAD frequency: 0.00011  dbSNP: rs200585833

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229337	SCV000288348	uncertain significance	Neuroblastoma, susceptibility to, 3	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1200 of the ALK protein (p.Ala1200Val). This variant is present in population databases (rs200585833, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 239825). 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.
Ambry Genetics	RCV000573898	SCV000672473	benign	Hereditary cancer-predisposing syndrome	2024-06-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000229337	SCV001299375	uncertain significance	Neuroblastoma, susceptibility to, 3	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.
Sema4, Sema4	RCV000573898	SCV002528484	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	curation
GeneDx	RCV002284382	SCV002574266	uncertain significance	not provided	2022-03-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31712133)
Baylor Genetics	RCV000229337	SCV004195507	uncertain significance	Neuroblastoma, susceptibility to, 3	2024-02-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745300	SCV005352643	uncertain significance	ALK-related disorder	2024-04-08	no assertion criteria provided	clinical testing	The ALK c.3599C>T variant is predicted to result in the amino acid substitution p.Ala1200Val. This variant has been reported in a tumor sample, but not in the germline, of an individual with neuroblastoma (Bresler SC et al 2014. PubMed ID: 25517749). An in vitro study showed that this variant had similar autophosphorylation properties as wild-type (Bresler SC et al 2014. PubMed ID: 25517749). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/239825/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.