ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1003G>T (p.Gly335Ter) (rs1555068471)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566562 SCV000660647 pathogenic Hereditary cancer-predisposing syndrome 2016-07-08 criteria provided, single submitter clinical testing The p.G335* pathogenic mutation (also known as c.1003G>T), located in coding exon 7 of the ATM gene, results from a G to T substitution at nucleotide position 1003. This changes the amino acid from a glycine to a stop codon within coding exon 7. 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.
Invitae RCV000689138 SCV000816778 pathogenic Ataxia-telangiectasia syndrome 2020-06-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly335*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000689138 SCV001339035 likely pathogenic Ataxia-telangiectasia syndrome 2020-03-10 criteria provided, single submitter clinical testing Variant summary: ATM c.1003G>T (p.Gly335X) 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 (e.g. c.1339C>T (p.Arg447X)). The variant was absent in 251174 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1003G>T in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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