ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3663G>A (p.Trp1221Ter) (rs864622490)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206039 SCV000260841 pathogenic Ataxia-telangiectasia syndrome 2019-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1221 (p.Trp1221*) of 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 been reported in individuals affected with ataxia-telangiectasia (PMID: 10330348, 22071889). ClinVar contains an entry for this variant (Variation ID: 220358). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235543 SCV000293436 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.3663G>A at the cDNA level and p.Trp1221Ter (W1221X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA) , and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the compound heterozygous state with pathogenic ATM variants in individuals with ataxia-telangiectasia (Teraoka 1999, Bernstein 2003, Jacquemin 2012, Hoche 2014) and is considered pathogenic.
Counsyl RCV000206039 SCV000487075 pathogenic Ataxia-telangiectasia syndrome 2016-10-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563523 SCV000672666 pathogenic Hereditary cancer-predisposing syndrome 2019-09-13 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000206039 SCV000918512 pathogenic Ataxia-telangiectasia syndrome 2018-02-08 criteria provided, single submitter clinical testing Variant summary: ATM c.3663G>A (p.Trp1221X) 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., p.Leu1238fsX6 and p.Arg1466X). The variant was absent in 120132 control chromosomes. The c.3663G>A variant has been reported in the literature in several compound heterozygous individuals affected with Ataxia-Telangiectasia. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000563523 SCV001342835 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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