ATM NM_000051.3:c.67C>T, Arg23Ter

The p.R23* pathogenic mutation (also known as c.67C>T), located in coding exon 1 of the ATM gene, results from a C to T substitution at nucleotide position 67. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been reported in the tumor and germline of an individual diagnosed with mantle cell lymphoma (Camacho E et al. Blood. 2002 Jan;99(1):238-44), and in a patient with gastric cancer (Huang DS et al. Oncotarget. 2015 Dec;6(38):40953-8). In addition to the clinical data 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.

This variant changes 1 nucleotide in exon 2 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the homozygous state or with a second pathogenic ATM variant in multiple individuals affected with ataxia-telangiectasia (PMID: 26896183, 33547824). This variant has also been reported in individuals affected with mantle cell lymphoma, gastric cancer, medulloblastoma, and breast cancer (PMID: 11756177, 26506520, 29753700, 31214711). This variant has been identified in 5/251364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Arg23*) 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 (rs746235533, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with lymphoma, gastric cancer, and medulloblastoma (PMID: 11756177, 26506520, 29753700). ClinVar contains an entry for this variant (Variation ID: 232248). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.

Variant summary: ATM c.67C>T (p.Arg23X) 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 2e-05 in 251364 control chromosomes (gnomAD). c.67C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (examples: Amirfar_2021 and Jackson_2016). These data indicate that the variant is very likely associated with disease. Jackson_2016 demonstrated the homozygous patient's lymphoblastoid cell lines showing ATM protein was present, kinase activity was absent and radiosensitivity was high. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.