Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001044327 | SCV001208118 | uncertain significance | Neuroblastoma, susceptibility to, 3 | 2023-09-22 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs753549939, gnomAD 0.0009%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 841997). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 372 of the ALK protein (p.Ala372Thr). |
| Department of Pathology and Laboratory Medicine, |
RCV001356602 | SCV001551817 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The ALK p.Ala372Thr variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs753549939). The variant was identified in control databases in 1 of 251212 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European (non-Finnish) in 1 of 113546 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Ala372 residue is not conserved in mammals and 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. |