Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000777655 | SCV000913542 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-10-22 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with threonine at codon 425 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248740 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 |
RCV001869128 | SCV002163619 | uncertain significance | Ataxia-telangiectasia syndrome | 2021-08-20 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with threonine at codon 425 of the ATM protein (p.Ala425Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs769214234, ExAC 0.002%). 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: 631432). 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 not expected to disrupt ATM protein function. 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 | RCV000777655 | SCV002688670 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-02-11 | criteria provided, single submitter | clinical testing | The p.A425T variant (also known as c.1273G>A), located in coding exon 9 of the ATM gene, results from a G to A substitution at nucleotide position 1273. The alanine at codon 425 is replaced by threonine, an amino acid with similar properties. This variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancer at age 41 and had a family history of breast cancer (Caminsky NG et al. Hum Mutat, 2016 07;37:640-52). This variant has also been detected in a homozygous state in a patient with primary ovarian insufficiency who was not noted to have features of ataxia-telangiectasia syndrome; however, detailed clinical information was not provided (França MM et al. PLoS One, 2020 Oct;15:e0240795). This amino acid position is poorly 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. |
| Baylor Genetics | RCV003465704 | SCV004209462 | uncertain significance | Familial cancer of breast | 2023-09-12 | criteria provided, single submitter | clinical testing |