ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222842 SCV000278020 pathogenic Hereditary cancer-predisposing syndrome 2016-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000169336 SCV000220682 likely pathogenic Ataxia-telangiectasia syndrome 2014-09-10 criteria provided, single submitter literature only
GeneDx RCV000519059 SCV000617365 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.802C>T at the cDNA level and p.Gln268Ter (Q268X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA) . In addition, ATM Gln268Ter has also been reported to result in skipping of exon 7, also defined as exon 9 using alternate exon numbering (Teraoka 1999). Both ATM Gln268Ter and skipping of exon 7 are predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM Gln268Ter has been reported in the compound heterozygous state with a second ATM variant in several individuals with A-T (Buzin 2003, Carranza 2017). Based on currently available evidence, we consider ATM Gln268Ter to be pathogenic.
Integrated Genetics/Laboratory Corporation of America 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 2018-12-08 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.

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