ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8307G>A (p.Trp2769Ter) (rs778269655)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169516 SCV000220986 likely pathogenic Ataxia-telangiectasia syndrome 2014-12-23 criteria provided, single submitter literature only
Invitae RCV000169516 SCV000260922 pathogenic Ataxia-telangiectasia syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp2769*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs778269655, ExAC 0.01%). This variant has been observed in an individual affected with ataxia-telangiectasia (PMID: 8845835). ClinVar contains an entry for this variant (Variation ID: 189104). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000579481 SCV000682476 pathogenic Hereditary cancer-predisposing syndrome 2020-11-17 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 57 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 individuals affected with breast cancer (PMID: 26786923) and in the compound heterozygous state with a second ATM mutation in individuals affected with ataxia telangiectasia (PMID: 8845835, 22649200). This variant has been identified in 2/251376 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.
Ambry Genetics RCV000579481 SCV001189935 pathogenic Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing The p.W2769* pathogenic mutation (also known as c.8307G>A), located in coding exon 56 of the ATM gene, results from a G to A substitution at nucleotide position 8307. This changes the amino acid from a tryptophan to a stop codon within coding exon 56. This mutation has been identified in several individuals with Ataxia-telangiectasia (AT) who also carried another mutation in the ATM gene (Gilad S, et al. Hum. Mol. Genet. 1996;5(4):433-9; Jackson TJ et al. Dev. Med. Child Neurol. 2016 07;58:690-7; Ambry internal data). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genetic. 2017 11;54:732-741) and was identified in 2/2000 Australian breast or ovarian cancer patients and 0/1997 controls undergoing multigene panel testing for hereditary cancer risk (Thompson ER et al, J. Clin. Oncol. 2016 May;34:1455-9). 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.
GeneDx RCV001564923 SCV001788165 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing 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 breast, colon, and prostate cancer (Thompson 2016, Decker 2017, Ghazani 2017, Na 2017, AlDubayan 2018, Li 2019); Observed in the compound heterozygous state in individuals with ataxia-telangiectasia (Gilad 1996, Corts 2003, Rbe 2010); Published functional studies demonstrate a damaging effect: absence of protein expression, loss of kinase activity, and increased sensitivity to ionizing radiation (Corts 2003); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 8845835, 25525159, 32338768, 27989354, 29752822, 33436325, 28125075, 28779002, 29478780, 29555025, 26786923, 28716242, 12883528, 20153123, 25133958)

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