Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000122825 | SCV000166082 | uncertain significance | Ataxia-telangiectasia syndrome | 2017-05-09 | criteria provided, single submitter | clinical testing | 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 135736). This sequence change replaces threonine with alanine at codon 616 of the ATM protein (p.Thr616Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. |
| Ambry Genetics | RCV000129264 | SCV000184024 | uncertain significance | Hereditary cancer-predisposing syndrome | 2013-11-23 | criteria provided, single submitter | clinical testing | ​The p.T616A variant (also known as c.1846A>G) is located in coding exon 11 of the ATM gene. This alteration results from a A to G substitution at nucleotide position 1846. The threonine at codon 616 is replaced by alanine, an amino acid with similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 5800 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. However, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.T616A remains unclear. |