Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000564504 | SCV000660512 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-04 | criteria provided, single submitter | clinical testing | The p.R2580K variant (also known as c.7739G>A), located in coding exon 51 of the ATM gene, results from a G to A substitution at nucleotide position 7739. The arginine at codon 2580 is replaced by lysine, an amino acid with highly similar properties. This variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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. |
| Color Diagnostics, |
RCV000564504 | SCV000682433 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-06-09 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with lysine at codon 2580 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/251114 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Labcorp Genetics |
RCV001218403 | SCV001390285 | pathogenic | Ataxia-telangiectasia syndrome | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2580 of the ATM protein (p.Arg2580Lys). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs761790685, gnomAD 0.03%). 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: 478937). 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. Studies have shown that this missense change results in skipping of exon 52, but is expected to preserve the integrity of the reading-frame (Invitae). This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg2547_Ser2549del) have been determined to be pathogenic (PMID: 7792600, 8797579, 11382771, 12552559, 21787400, 22649200). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Natera, |
RCV001218403 | SCV002083589 | uncertain significance | Ataxia-telangiectasia syndrome | 2020-03-07 | no assertion criteria provided | clinical testing |