Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000647410 | SCV000769206 | uncertain significance | Neuroblastoma, susceptibility to, 3 | 2025-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1553 of the ALK protein (p.Ala1553Gly). This variant is not present in population databases (gnomAD no frequency). 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: 538207). 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. |
| Ambry Genetics | RCV002331218 | SCV002633713 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-05-10 | criteria provided, single submitter | clinical testing | The p.A1553G variant (also known as c.4658C>G), located in coding exon 29 of the ALK gene, results from a C to G substitution at nucleotide position 4658. The alanine at codon 1553 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV001357167 | SCV001552540 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The ALK p.Ala1553Gly variant was not identified in the literature nor was it identified in dbSNP, Cosmic or LOVD 3.0. The variant was identified in ClinVar (classified as a VUS by Invitae). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (March 6, 2019, v2.1.1). The p.Ala1553 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |