Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001214195 | SCV001385866 | uncertain significance | Neuroblastoma, susceptibility to, 3 | 2022-09-01 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 943911). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This sequence change affects a donor splice site in intron 20 of the ALK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ALK cause disease. |
| Ambry Genetics | RCV002322036 | SCV002607252 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-09-24 | criteria provided, single submitter | clinical testing | The c.3359+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 20 of the ALK gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of ALK has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |