Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000822674 | SCV000963484 | uncertain significance | Ataxia-telangiectasia syndrome | 2023-08-07 | criteria provided, single submitter | clinical testing | 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. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 511 of the ATM protein (p.Ile511Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 664559). 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. |
| Ambry Genetics | RCV002397726 | SCV002708274 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-27 | criteria provided, single submitter | clinical testing | The p.I511V variant (also known as c.1531A>G), located in coding exon 9 of the ATM gene, results from an A to G substitution at nucleotide position 1531. The isoleucine at codon 511 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in an unaffected individual who underwent multigene panel testing for hereditary cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol 2021 Mar;147(3):871-879). This amino acid position is well conserved in available vertebrate species. 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, |
RCV001354251 | SCV001548816 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The ATM p.Ile511Val variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, COGR, Cosmic, MutDB, LOVD 3.0, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Ile511 residue is conserved in in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. |