Submissions for variant NM_004304.5(ALK):c.4795C>T (p.Pro1599Ser)

gnomAD frequency: 0.00013  dbSNP: rs373037272

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470897	SCV000541843	uncertain significance	Neuroblastoma, susceptibility to, 3	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1599 of the ALK protein (p.Pro1599Ser). This variant is present in population databases (rs373037272, gnomAD 0.03%). 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: 404336). 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.
Illumina Laboratory Services, Illumina	RCV000470897	SCV001299242	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV002298594	SCV002588211	uncertain significance	not provided	2022-04-29	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
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000470897	SCV003843148	uncertain significance	Neuroblastoma, susceptibility to, 3	2022-11-07	criteria provided, single submitter	clinical testing	The ALK c.4795C>T( p.Pro1599Ser) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with ALK-related neuroblastic tumor susceptibility. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV000470897	SCV004197931	uncertain significance	Neuroblastoma, susceptibility to, 3	2023-10-14	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000470897	SCV004228699	not provided	Neuroblastoma, susceptibility to, 3		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-29-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.