Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001937703 | SCV002185826 | uncertain significance | Ataxia-telangiectasia syndrome | 2021-08-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with arginine at codon 2867 of the ATM protein (p.Gly2867Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 8698354). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATM protein function. Experimental studies have shown that this missense change affects ATM function (PMID: 11805335, 15279808). 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 | RCV002449567 | SCV002679923 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-06-08 | criteria provided, single submitter | clinical testing | The p.G2867R variant (also known as c.8599G>C), located in coding exon 58 of the ATM gene, results from a G to C substitution at nucleotide position 8599. The glycine at codon 2867 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in the heterozygous state in an individual with classical ataxia-telangiectasia, who did not have a second ATM alteration identified (Sandoval N et al. Hum Mol Genet, 1999 Jan;8:69-79). Functional studies have indicated that this alteration disrupts ATM kinase activity and increases radiosensitivity (Scott SP et al. Proc Natl Acad Sci U S A, 2002 Jan;99:925-30). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Bareti D et al. Sci Adv, 2017 May;3:e1700933). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Gene |
RCV003232459 | SCV003929569 | uncertain significance | not provided | 2022-12-01 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in an individual with ataxia telangiectasia (Baumer et al., 1996; Sandoval et al., 1999); Published functional studies demonstrate a damaging effect: failure to elicit ATM kinase activity and enhanced radiosensitivity (Scott et al., 2002); This variant is associated with the following publications: (PMID: 15279808, 23532176, 34771661, 9259193, 9887333, 22529920, 11805335, 8698354) |
| Center for Genomic Medicine, |
RCV003493892 | SCV004242561 | uncertain significance | not specified | 2024-02-06 | criteria provided, single submitter | clinical testing |