ClinVar Genomic variation as it relates to human health

Observed with a second ATM variant in individuals with ataxia telangiectasia (Babaei et al., 2005; Broccoletti et al., 2011); Observed in the heterozygous state in individuals with ATM-related cancers referred for genetic testing at GeneDx and in published literature (Siraj et al., 2017); 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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10330348, 26662178, 29922827, 16266405, 25502423, 15390180, 20840352, 15843990, 14970866, 28975465, 28779002, 31850668, 21665257, 22763152, 10425038, 11839094, 33779842)

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

The c.381delA pathogenic mutation (also known as p.V128*), located in coding exon 4 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 381. This changes the amino acid from a valine to a stop codon within coding exon 4. This mutation has been reported in multiple ataxia-telangiectasia (A-T) families to date (Babaei M et al. Hum. Genet. 2005 Jul;117(2-3):101-6; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Podralska MJ et al. Mol. Genet. Genomic Med. 2014 Nov;2(6):504-11) as well as an in a high-risk melanoma cohort (Stolarova L et al. Biomedicines, 2020 Oct;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.

Criteria applied: PVS1,PM2_SUP,PM5_SUP

The c.381delA variant has been previously reported in association with ataxia telangiectasia in multiple unrelated families (Mitui 2005, and Babaei 2005). The c.381delA variant creates a frameshift in the ATM protein at codon 128 in exon 5 which results in a premature termination codon and is predicted to result in a truncated or absent protein product. It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP) , and the Exome Aggregation Consortium (ExAC) browser but has been reported to ClinVar (Variation ID: 141546). Based on these observations, the c.381delA variant has been classified as pathogenic.

The ATM c.381delA (p.Val128Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Val128Ter variant has been found in at least six individuals with ataxia-telangiectasia, all in a compound heterozygous state (Babaei et al. 2005; Mitui et al. 2005; Quarantelli et al. 2013; Podralska et al. 2014). Control data are not available for this variant, which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and the potential impact of frameshift variants, the p.Val128Ter variant is classified as pathogenic for ataxia-telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The c.381delA (p.Val128*) variant in the ATM gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has an extremely low frequency in large databases of genetic variation in the general population. This variant has been reported in multiple patients with Ataxia-telangiectasia (PMID 10425038, 15843990, 16266405 and 25614872). Experimental studies in heterozygous cell lines suggested that this variant leads to reduced ATM protein expression following exposure to radiation (PMID 14970866). Bi-allelic variants in the ATM gene are associated with Ataxia-telangiectasia (MIM #208900). Therefore, the c.381delA (p.Val128*) variant in the ATM gene is classified as pathogenic.

Variant summary: ATM c.381delA (p.Val128X) 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 251238 control chromosomes. c.381delA has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (examples: Broccoletti_2011, Micol_2011, Mitui_2005, Al-Muhaizea_2022, etc). Experimental evidence evaluating an impact on protein function, demonstrated the variant to result in an overall reduced ATM protein level, mRNA level and cell survival after exposure to ionizing radiation (Fernet_2004). 16 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Val128*) 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 (rs587781831, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 15843990, 16266405, 25502423, 25614872). This variant is also known as c.380delA and c.381_381delA. ClinVar contains an entry for this variant (Variation ID: 141546). For these reasons, this variant has been classified as Pathogenic.

This variant deletes 1 nucleotide in exon 5 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 10330348, 10425038, 11839094, 15843990, 20840352). This variant has been identified in 1/251238 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.

A known pathogenic mutation was detected in the ATM gene(p.Val128Ter). This sequence change creates a premature translational stop signal (p.Val128*) 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 (rs587781831, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 15843990, 16266405, 25502423, 25614872). This variant is also known as c.380delA and c.381_381delA. ClinVar contains an entry for this variant (Variation ID: 141546). For these reasons, this variant has been classified as Pathogenic. Pathogenic germline variants in the ATM gene are associated to increased breast cancer risk and further ATM-related malignancies. The cancer risk of individuals heterozygous for an ATM pathogenic variant is approximately four times that of the general population. Cancer risk probably depends on multiple factors including tumor type, age at cancer onset, and whether the type of variant (PMID: 20301790, OMIM® 114480). According to NCCN guidelines (version 3.2023), pathogenic or likely pathogenic variants in this gene are associated with 6% by age 50 years and 33% by age 80 years lifetime risk of breast cancer. The risk increases with increasing number of relatives affected with breast cancer. Hereditary predisposition to cancer due to pathogenic variants in the ATM gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. In addition, ATM, ATM serine/threonine kinase, is a member of the serine-threonine kinase family and coordinates cellular responses to DNA damage through activation of distinct DNA repair and signaling pathways (PMID: 22079189). ATM germline mutations are associated also with ataxia telangiectasia, an autosomal recessive disorder (OMIM®: 208900, PMID: 27283171). Furthermore, Roberts et al., 2012 published a study indicating that ATM variants play an important role in familial pancreatic cancer predisposition (PMID: 22585167: PMID: 34529012).