Submissions for variant NM_004304.5(ALK):c.782G>A (p.Arg261Gln)

dbSNP: rs375097381

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460065	SCV000541873	uncertain significance	Neuroblastoma, susceptibility to, 3	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 261 of the ALK protein (p.Arg261Gln). This variant is present in population databases (rs375097381, 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: 404364). 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.
GeneDx	RCV003225068	SCV003921371	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003401448	SCV004104032	uncertain significance	ALK-related disorder	2022-09-23	criteria provided, single submitter	clinical testing	The ALK c.782G>A variant is predicted to result in the amino acid substitution p.Arg261Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-29940449-C-T) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/404364/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004948303	SCV005589410	likely benign	Hereditary cancer-predisposing syndrome	2024-08-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Fulgent Genetics, Fulgent Genetics	RCV000460065	SCV005649288	uncertain significance	Neuroblastoma, susceptibility to, 3	2024-06-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003151057	SCV003839515	uncertain significance	not specified	2022-07-12	no assertion criteria provided	clinical testing	DNA sequence analysis of the ALK gene demonstrated a sequence change, c.782G>A, in exon 2 that results in an amino acid change, p.Arg261Gln. This sequence change does not appear to have been previously described in individuals with ALK-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.016% in the South Asian subpopulation and 0.0046% in the overall population (dbSNP rs375097381). The p.Arg261Gln change affects a moderately conserved amino acid residue located in a domain of the ALK protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg261Gln substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg261Gln change remains unknown at this time.