ClinVar Genomic variation as it relates to human health

Variant summary: ATM c.7456C>T (p.Arg2486X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251264 control chromosomes. c.7456C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Buzin_2003, Micol_2011, Meneret_2014). Heterozygous mutations in ATM are a risk allele for malignancies, and this mutation has also been reported in the literature in individuals with breast and other cancers (Takai_2016, Susswein_2016, Sun_2017, Ohmoto_2018, and Yang_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Arg2486*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs587779865, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 12552559, 26681312, 27732944, 28724667). ClinVar contains an entry for this variant (Variation ID: 127445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The p.R2486* pathogenic mutation (also known as c.7456C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7456. This changes the amino acid from an arginine to a stop codon within coding exon 49. This mutation has been identified in multiple patients with ataxia-telangiectasia, either in a homozygous or compound heterozygous state (Buzin CH et al. Hum Mutat, 2003 Feb;21:123-31; Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1; Méneret A et al. Neurology, 2014 Sep;83:1087-95; Berland A et al. J Allergy Clin Immunol, 2019 01;143:325-334.e2; Fiévet A et al. Hum Mutat, 2019 10;40:1713-1730). This mutation has also been reported in multiple patients with breast or pancreatic cancer (Susswein LR et al. Genet Med, 2016 08;18:823-32; Takai E et al. Oncotarget, 2016 Nov;7:74227-74235; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Ohmoto A et al. J Gastroenterol, 2018 Oct;53:1159-1167; Yang Z et al. Breast Cancer Res Treat, 2019 Apr;174:639-647). In addition to the information presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

A heterozygous nonsense variant in exon 50 of the ATM gene that results in a stop codon and premature truncation of the protein at codon 2486 (p.Arg2486Ter) was detected. The observed variant has previously been reported in patients affected with ataxia telangiectasia [PMID: 25122203]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1) and gnomdAD (v2) databases and has a minor allele frequency of 0.0008% in the topmed database. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

The stop gained c.7456C>T (p.Arg2486Ter) variant in ATM gene has been reported previously in homozygous state in patients affected with AtaxiaTelangiectasia (Buzin CH et al.,2003). This variant has been reported to the ClinVar database as Pathogenic/Likely_pathogenic. This variant has been submitted allele frequency 0.001194 % in the gnomAD and novel in 1000 genome database. The nucleotide change c.7456C>T in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in the heterozygous state in individuals with ATM-related cancers (PMID: 27732944, 28724667, 29667044); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25525159, 26681312, 27479817, 25122203, 27732944, 30607632, 31050087, 28724667, 12552559, 29667044, 29922827, Dorgaleleh2022[article], 35118230, 36243179, 29906526, 32826389, 35729272, 35260754, 21665257)