ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.802C>T (p.Gln268Ter) (rs557012154)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169336 SCV000220682 likely pathogenic Ataxia-telangiectasia syndrome 2014-09-10 criteria provided, single submitter literature only
Ambry Genetics RCV000222842 SCV000278020 pathogenic Hereditary cancer-predisposing syndrome 2018-07-06 criteria provided, single submitter clinical testing The p.Q268* pathogenic mutation (also known as c.802C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 802. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation has been previously identified in ataxia-telangiectasia patients (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31. 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 RCV000519059 SCV000617365 pathogenic not provided 2019-11-20 criteria provided, single submitter clinical testing Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Teraoka 1999); Published functional studies demonstrate a damaging effect: loss of kinase activity (Carranza 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 10330348, 27664052, 12552559, 25525159)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169336 SCV000694369 likely pathogenic Ataxia-telangiectasia syndrome 2016-09-26 criteria provided, single submitter clinical testing Variant summary: The ATM c.802C>T (p.Gln268X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, this variant will be expected to truncate the catalytic and FAT domains and armadillo-type fold (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp393X, p.Gln1017X etc.). This variant was found in 2/125724 control chromosomes at a frequency of 0.0000159, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). In literature, this variant has been reported in two patients with Ataxia-Telangiectasia in compound heterozygous with another variant (Teraoka_1999, Buzin_2003). Functional analysis using nested-PCR cDNAs of a cell line containing this variant showed missplicing of exon 9 (Teraoka_1999). The effect was the partial skipping of the exon. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Likely Pathogenic.
Invitae RCV000169336 SCV000749006 pathogenic Ataxia-telangiectasia syndrome 2020-09-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln268*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs557012154, ExAC 0.002%). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 10330348, 12552559). ClinVar contains an entry for this variant (Variation ID: 188961). 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 RCV000222842 SCV001347034 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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