Submissions for variant NM_004304.5(ALK):c.3057C>A (p.Val1019=)

gnomAD frequency: 0.00043  dbSNP: rs138406372

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001001870	SCV000429938	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV001001870	SCV000554755	benign	Neuroblastoma, susceptibility to, 3	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001706548	SCV000718365	benign	not provided	2019-08-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28873162)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001870	SCV001159592	benign	Neuroblastoma, susceptibility to, 3	2018-09-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018354	SCV001179580	benign	Hereditary cancer-predisposing syndrome	2018-09-14	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000607579	SCV001362955	benign	not specified	2019-05-14	criteria provided, single submitter	clinical testing	Variant summary: ALK c.3057C>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0026 in 251350 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 6216 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALK causing Neuroblastoma, Susceptibility Type 3 phenotype (4.2e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3057C>A in individuals affected with Neuroblastoma, Susceptibility Type 3 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign (n=1), likely benign (n=2)). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000607579	SCV002070891	benign	not specified	2021-07-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001001870	SCV002802972	likely benign	Neuroblastoma, susceptibility to, 3	2022-05-24	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001001870	SCV004016777	benign	Neuroblastoma, susceptibility to, 3	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001706548	SCV004144032	benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ALK: BP4, BS1, BS2