ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5825C>T (p.Ala1942Val) (rs730881394)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159768 SCV000209789 uncertain significance not provided 2018-06-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.5825C>T at the cDNA level, p.Ala1942Val (A1942V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant was observed, presumably, in the compound heterozygous state in an atypical case of Ataxia-Telangiectasia (A-T) with a diagnosis of pancreatic cancer at age 48 as well as in two cases described as classical A-T reported to have no detectable ATM protein activity (Davis 2013, Carney 2012). ATM Ala1942Val was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ala1942Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000218056 SCV000274727 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-08 criteria provided, single submitter clinical testing The p.A1942V variant (also known as c.5825C>T), located in coding exon 38 of the ATM gene, results from a C to T substitution at nucleotide position 5825. The alanine at codon 1942 is replaced by valine, an amino acid with similar properties. This alteration has been detected in conjunction with the ATM mutation, c.7638_7646delTAGAATTTC, in two siblings with ataxia-telangiectasia (A-T) (Carney EF et al. J Immunol. 2012 Jul;189:261-8). Functional assays performed on their cells showed a high level of chromosomal radiosensitivity and absence of ATM kinase activity (Carney EF et al. J Immunol. 2012 Jul;189:261-8). The ATM p.A1942V variant has also been reported in conjunction with the ATM mutation, c.1898+2T>G, in a second individual with A-T (Davis MY et al. J. Neurol. Sci. 2013 Dec;335:134-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000463126 SCV000547006 pathogenic Ataxia-telangiectasia syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1942 of the ATM protein (p.Ala1942Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with ataxia telangiectasia (A-T) (PMID: 22649200, 24090759, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 181999). This variant has been reported to affect ATM protein function (PMID: 22649200). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000463126 SCV000798043 uncertain significance Ataxia-telangiectasia syndrome 2018-02-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000218056 SCV000913974 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-08 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 1942 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported in two individuals affected with classic ataxia telangiectasia in compound heterozygosity with a pathogenic c.7638_7646del mutation (PMID: 22649200). Cells from these patients showed significantly reduced levels of ATM protein (5% of wild type) and undetectable ATM kinase activity (PMID: 22649200). This variant has also been reported in compound heterozygosity with a pathogenic splice variant in an individual affected with a mild form of ataxia telangiectasia, who died at age 48 with pancreatic adenocarcinoma (PMID: 24090759). This variant has been identified in 1/251070 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.