ClinVar Genomic variation as it relates to human health

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 individuals with ataxia-telangiectasia in the apparent homozygous and compound heterozygous states, and cell lines from some of these patients displayed impaired phosphorylation and DNA damage response, and reduced ATM protein expression (Gilad et al., 1998; Becker-Catania 2000; Keimling et al., 2011); Observed in individuals with ATM-related cancers (Hollestelle et al., 2010; Tung et al., 2016; Decker et al., 2017; Whitworth et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26976419, 35047863, 10330348, 21787400, 24008619, 20346647, 27980538, 28779002, 29909963, 30549301, 9450906, 30322717, 32255556, 29625052, 34426522, 25525159, 33436325, 29922827, 33804961, 26896183, 28888541, 10873394, 21778326)

This sequence change creates a premature translational stop signal (p.Arg1875*) 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 (rs376603775, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9450906, 10873394, 21792198, 26976419, 27980538). ClinVar contains an entry for this variant (Variation ID: 245815). For these reasons, this variant has been classified as Pathogenic.

The p.R1875* pathogenic mutation (also known as c.5623C>T), located in coding exon 36 of the ATM gene, results from a C to T substitution at nucleotide position 5623. This changes the amino acid from an arginine to a stop codon within coding exon 36. This mutation has been reported in both the homozygous and compound heterozygous state in multiple patients with ataxia-telangiectasia (A-T) (Becker-Catania SG et al. Mol Genet Metab, 2000 Jun;70:122-33; Cummins G et al. Parkinsonism Relat Disord, 2013 Dec;19:1173-4; Sheikhbahaei S et al. Allergy Asthma Clin Immunol. 2016 Dec 2;12:62). One study, in an A-T patient who was positive for this mutation along with another truncation ATM alteration, demonstrated residual ATM protein expression and activity was reportedly absent (Carney EF et al. J. Immunol. 2012 Jul; 189(1):261-8). This mutation has been detected in patients with multiple cancer types including breast, ovarian, pancreatic, prostate and melanoma (Tavtigian SV et al. Am J Hum Genet, 2009 Oct;85:427-46; Decker B et al. J Med Genet, 2017 11;54:732-741; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Cremin C et al. Cancer Med, 2020 06;9:4004-4013; Feliubadaló L et al. Clin Chem, 2021 03;67:518-533; Dorling et al. N Engl J Med. 2021 02;384:428-439; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). Furthermore, tumor studies have revealed loss of heterozygosity (LOH) associated with this mutation (Goldgar DE et al. Breast Cancer Res. 2011; 13(4):R73). 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.

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

This variant creates a premature stop codon. The variant transcript is predicted to be degraded by nonsense-mediated decay or lead to a truncated protein. Loss of expression of one allele of ATM is a well-established mechanism of disease (Huang2013, Podralska 2014). This variant has been reported in the literature in an individual with breast cancer (Tung 2016) and in individuals with ataxia-telangiectasia (Gilad 1998, Becker-Catania 2000, Reiman 2011). This variant has an allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PP3

The c.5623C>T (p.Arg1875*) variant in exon 37 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 individuals with ataxia telangiectasia (PMID 9450906, 22649200) and multiple individuals with breast cancer (PMID 19781682, 20346647, 21787400,26976419). This variant is extremely rare in a heterozygous state in a large population database (gnomAD). Therefore, the c.5623C>T (p.Arg1875*) variant in the ATM gene is classified as pathogenic.

The c.5623C>T (p.Arg1875*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0013%, (3/235,362 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0020%, (2/102100 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This variant has been reported in at least three ataxia-telangiectasia probands together with (likely) pathogenic variants (PMID: 21792198, 22649200, 21778326) and in two homozygous probands (PMID: 10873394, 9450906), which awards it with at least 2 points as per ClinGen SVI Recommendation for in trans Criterion (PM3_Strong; PMID: 21965147). Assays performed with lymphoblastoid cell lines of an homozygous and a compound heterozygous ataxia-telangiectasia patients showed reduced levels (PMID: 10873394) and absence (PMID: 21778326) of ATM protein, respectively. Additionally, very little phosphorylation of SMC1, KAP1, and CHK2 proteins was observed in the latter patient (PS3_Moderate, PMID: 21778326). c.1463G>A Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_Strong + PS3_Moderate (PMID: 33280026)

Variant summary: ATM c.5623C>T (p.Arg1875X) 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 249754 control chromosomes. c.5623C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (example, Gilad_1998, Becker-Catnia_2000, Reiman_2011, Sheikhbahaei_2016). These data indicate that the variant is very likely to be associated with disease. Nine 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.

This variant changes 1 nucleotide in exon 37 of the ATM gene, creating a 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 observed in individuals affected with breast cancer (PMID: 19781682, 21787400, 26976419, 28779002, 33471991), pancreatic cancer (PMID: 32255556), and in homozygous and compound heterozygous carriers affected with ataxia-telangiectasia (PMID: 9450906, 10873394, 21792198, 21792198, 30549301). This variant has been identified in 5/249754 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 variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.