ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.217_218del (p.Glu73fs) (rs762089971)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000690228 SCV000817907 pathogenic Ataxia-telangiectasia syndrome 2018-06-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu73Metfs*26) in the ATM gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in the homozygous state in an individual affected with ataxia telangiectasia (PMID: 10817650). This variant is also known as 216delAG in the literature. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000690228 SCV000916574 pathogenic Ataxia-telangiectasia syndrome 2018-04-16 criteria provided, single submitter clinical testing Variant summary: ATM c.217_218delGA (p.Glu73MetfsX26) 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 (eg. c.513C>G (p.Tyr171X), c.790delT (p.Tyr264fsX12), and c.1027_1030delGAAA (p.Glu343fsX2)). The variant of interest was observed with an allele frequency of 7.2e-06 in 275964 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (7.2e-06 vs 0.004), allowing no conclusion about variant significance. The variant, c.217_218delGA, has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Li_2000, Carney_2012), which one compound heterozygote pt was found to have no ATM protein expression (Carney_2012). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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