ATM NM_000051.3:c.2413C>T, Arg805Ter

The p.R805* pathogenic mutation (also known as c.2413C>T), located in coding exon 15 of the ATM gene, results from a C to T substitution at nucleotide position 2413. This changes the amino acid from an arginine to a stop codon within coding exon 15. This alteration has been reported in multiple individuals with a clinical diagnosis of ataxia telangiectasia (Vorechovský I et al. Eur. J. Hum. Genet. 1996;4(6):352-5; Mitui M et al. Hum Mutat. 2003 Jul;22:43-50; Babaei M et al. Hum Genet. 2005 Jul;117:101-6; Cavalieri S et al. Hum. Mutat. 2006 Oct;27(10):1061; Chessa L et al. Ann. Hum. Genet. 2009 Sep;73(Pt 5):532-9; Huang Y et al. Neuromolecular Med. 2013 Sep;15(3):536-40; Ng PS et al. Clin Genet. 2016 10;90:315-23; Suspitsin E et al. Eur J Med Genet. 2020 Jan;63:103630). This alteration was also reported in several breast and/or ovarian cohorts (Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22(11):1305-13; Ng PS et al. Clin. Genet. 2016 Oct;90:315-23; Decker B et al. J. Med. Genet. 2017 Nov;54(11):732-741; Kwong A et al. J Mol Diagn. 2020 04;22:544-554). This alteration was also identified in a Chinese male with colon cancer diagnosed at 37 and a family history of colon, cecum, and ovarian cancer (Ow SGW et al. Clin Colorectal Cancer. 2019 12;18:e324-e334). 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 16 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 multiple individuals with ataxia-telangiectasia in homozygous or compound heterozygous state with other known pathogenic ATM variants (PMID: 12815592, 15843990, 16941484, 19691550, 21665257, 23807571, 30772474). This variant has also been reported in individuals with breast and/or ovarian cancer (PMID: 26757417, 32068069, 32566746). In a large international case-control study, this variant was reported in 6/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 10/251214 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.

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This sequence change creates a premature translational stop signal (p.Arg805*) 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 (rs780619951, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and a personal or family history of breast or ovarian cancer (PMID: 9043869, 12815592, 15843990, 16941484, 19691550, 24549055). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 216021). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Inviate). For these reasons, this variant has been classified as Pathogenic.

The c.2413C>T variant in ATM is a nonsense variant predicted to introduce a stop codon at amino acid 805. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 21445571). Given the available evidence, this variant is classified as Pathogenic.