ClinVar Genomic variation as it relates to human health

The c.3214G>T (p.Glu1072*) variant in exon 22 of the ATM gene introduces a premature termination codon and is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been observed in at least two patients with ataxia telangiectasia for which the second allele is both known to be in trans, and is a pathogenic variant (PMID 21833744 and 16266405). This variant is has been observed only once in a heterozygous state in a large population database (gnomAD). Therefore, the c.3214G>T (p.Glu1072*) variant in the ATM gene is classified as pathogenic.

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

Variant summary: ATM c.3214G>T (p.Glu1072X) 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 4e-06 in 251360 control chromosomes. c.3214G>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Soukupova_2011, Mitui_2005, Jackson_2016). These data indicate that the variant is likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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; Not observed at significant frequency in large population cohorts (gnomAD); Identified in the heterozygous state in individuals with pancreatic cancer (Roberts et al., 2012; Hutchings et al., 2019); This variant is associated with the following publications: (PMID: 8808599, 22585167, 25525159, 9443866, 30579816, 21833744, 31285527, 16266405)

This sequence change creates a premature translational stop signal (p.Glu1072*) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9443866, 22585167). ClinVar contains an entry for this variant (Variation ID: 407699). 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.

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

The p.E1072* pathogenic mutation (also known as c.3214G>T), located in coding exon 21 of the ATM gene, results from a G to T substitution at nucleotide position 3214. This changes the amino acid from a glutamic acid to a stop codon within coding exon 21. This mutation has been detected in conjunction with a second ATM alteration in numerous patients with Ataxia-Telangiectasia (A-T) (Wright J et al. Am. J. Hum. Genet., 1996 Oct;59:839-46; Telatar M et al. Am. J. Hum. Genet., 1998 Jan;62:86-97; Teraoka SN et al. Am J Hum Genet, 1999 Jun;64:1617-31; Mitui M et al. Ann. Hum. Genet., 2005 Nov;69:657-64; Soukupova J et al. Neuromolecular Med., 2011 Sep;13:204-11; Paucar M et al. Parkinsonism Relat Disord, 2019 05;62:253-255). This mutation has also been detected in patients with pancreatic and ovarian cancer (Roberts NJ et al. Cancer Discov, 2012 Jan;2:41-6; Harter P et al. PLoS One, 2017 Oct;12:e0186043; Hutchings D et al. Mod Pathol, 2019 12;32:1806-1813). 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.