ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.513C>G (p.Tyr171Ter) (rs786201693)

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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 RCV000164103 SCV000214716 pathogenic Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing ​The p.Y171* pathogenic mutation (also known as c.513C>G), located in coding exon 5 of the ATM gene, results from a C to G substitution at nucleotide position 513. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This alteration was identified in a German individual with ataxia-telangiectasia (Sandoval N et al. Hum. Mol. Genet. 1999; 8:69-79). 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 RCV000520700 SCV000617363 pathogenic not provided 2020-01-23 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 19022408, 9887333, 21778326, 28152038)
Invitae RCV000533506 SCV000622567 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr171*) 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 been observed in an individual affected with ataxia-telangiectasia (PMID: 9887333). ClinVar contains an entry for this variant (Variation ID: 184787). Experimental studies have shown that this nonsense change disrupts ATM protein function (PMID: 21778326). 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 RCV000533506 SCV000694299 pathogenic Ataxia-telangiectasia syndrome 2016-09-29 criteria provided, single submitter clinical testing Variant summary: The ATM c.513C>G (p.Tyr171X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM 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.Arg2506fsX3, p.Lys2756X). Mutation taster predicts a damaging outcome for this variant. This variant was absent in 43866 control chromosomes while it was found in at least one AT patient in homozygosity, indicating causality. In addition, a study reported ATM to be undetected in LCLs derived from an AT patient carying the variant of interest in homozygosity; these LCLs also had deregulated SSA and HDR, and were deficient in phosphorylation of SMC1, KAP1, and Chk2, further supporting pathogenicity. Moreover, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000533506 SCV000795016 likely pathogenic Ataxia-telangiectasia syndrome 2017-10-24 criteria provided, single submitter clinical testing

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