Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000800227 | SCV000939927 | uncertain significance | Ataxia-telangiectasia syndrome | 2023-01-16 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 646022). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 884 of the ATM protein (p.Pro884Ala). |
| Ambry Genetics | RCV002458456 | SCV002739039 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-22 | criteria provided, single submitter | clinical testing | The p.P884A variant (also known as c.2650C>G), located in coding exon 17 of the ATM gene, results from a C to G substitution at nucleotide position 2650. The proline at codon 884 is replaced by alanine, an amino acid with highly similar properties. This variant was detected in a woman diagnosed with breast cancer at age 27 (Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Breakthrough Genomics, |
RCV004693286 | SCV005191491 | uncertain significance | not provided | criteria provided, single submitter | not provided | ||
| Department of Pathology and Laboratory Medicine, |
RCV001358449 | SCV001554183 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The ATM p.Pro884Ala variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Pro884 residue is conserved in mammals, but not lower organisms with the variant amino acid Alanine (Ala) present in Zebrafish, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. | |
| Natera, |
RCV000800227 | SCV002078805 | uncertain significance | Ataxia-telangiectasia syndrome | 2021-08-10 | no assertion criteria provided | clinical testing |