Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000021080 | SCV001557198 | uncertain significance | Neuroblastoma, susceptibility to, 3 | 2023-07-06 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects ALK function (PMID: 21804922, 25517749). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 21867). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18724359). This variant is present in population databases (rs113994092, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1250 of the ALK protein (p.Ile1250Thr). 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 | RCV002345252 | SCV002621975 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-13 | criteria provided, single submitter | clinical testing | The p.I1250T variant (also known as c.3749T>C), located in coding exon 25 of the ALK gene, results from a T to C substitution at nucleotide position 3749. The isoleucine at codon 1250 is replaced by threonine, an amino acid with similar properties. This alteration was observed in the germline of a individual with neuroblastoma who had at least one other relative with neuroblastoma; however, this alteration has also been observed in unaffected individuals (Mossé YP et al. Nature, 2008 Oct;455:930-5; Ambry internal data). Functional studies demonstrate that p.I1250T is inactivating and has the potential to act as a dominant-negative receptor; however, its association with disease is unclear (Schönherr C et al. Transl Oncol, 2011 Aug;4:258-65; Bresler SC et al. Cancer Cell, 2014 Nov;26:682-94; Ma Y et al. Oncogene, 2016 11;35:6132-6142). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Gene |
RCV000021080 | SCV000041746 | not provided | Neuroblastoma, susceptibility to, 3 | no assertion provided | literature only | ||
Database of Curated Mutations |
RCV000440760 | SCV000510529 | likely pathogenic | Neuroblastoma | 2016-05-13 | no assertion criteria provided | literature only |