Submissions for variant NM_004304.5(ALK):c.4596C>T (p.Asn1532=)

gnomAD frequency: 0.01874  dbSNP: rs1881422

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001080667	SCV000429913	benign	Neuroblastoma, susceptibility to, 3	2018-01-12	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV001080667	SCV000554728	benign	Neuroblastoma, susceptibility to, 3	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575366	SCV000672459	benign	Hereditary cancer-predisposing syndrome	2018-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590798	SCV000698299	benign	not provided	2016-08-24	criteria provided, single submitter	clinical testing	Variant summary: The ALK c.4596C>T (p.Asn1532Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. In addition, ESE finder predicts that this variant may not affect ESE sites. This variant was found in 684/121410 control chromosomes (17 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0620796 (646/10406). This frequency is about 148991 times the estimated maximal expected allele frequency of a pathogenic ALK variant (0.0000004), suggesting this is likely a common benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign.
GeneDx	RCV000612129	SCV000731054	benign	not specified	2017-02-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001080667	SCV004016755	benign	Neuroblastoma, susceptibility to, 3	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001080667	SCV004562890	benign	Neuroblastoma, susceptibility to, 3	2023-11-22	criteria provided, single submitter	clinical testing