ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3057C>A (p.Val1019=) (rs138406372)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001001870 SCV000429938 benign Neuroblastoma 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 3 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000607579 SCV000718365 likely benign not specified 2017-12-19 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001870 SCV001159592 benign Neuroblastoma 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 General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Integrated Genetics/Laboratory Corporation of America 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.

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