ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5228C>T (p.Thr1743Ile) (rs587779844)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115208 SCV000149117 likely pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.5228C>T at the cDNA level, p.Thr1743Ile (T1743I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has been observed in at least four individuals with recessively-inherited Ataxia Telangiectasia (A-T), two individuals with breast cancer, one individual with colon cancer, and as a germline variant in an individual with chronic lymphocytic leukemia (Stankovic 1998, Tavtigian 2009, Reiman 2011, Skowronska 2012, Pearlman 2017). While it is not specified in the literature if ATM Thr1743Ile is on the opposite allele (in trans) as the other identified ATM variant in the individuals with A-T, it has been confirmed as in trans at another clinical laboratory (Stankovic 1998, Reiman 2011, ClinVar SCV000272973.4). Additionally, Barone et al. (2009) reported ATM Thr1743Ile to have reduced, but not absent, kinase activity. ATM Thr1743Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider ATM Thr1743Ile to be a likely pathogenic variant.
Invitae RCV000168297 SCV000218976 likely pathogenic Ataxia-telangiectasia syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1743 of the ATM protein (p.Thr1743Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs587779844, ExAC 0.003%). This variant has been observed in individuals affected with ataxia-telangiectasia (A-T) (PMID: 9463314, 21792198, 19147735), chronic lymphocytic leukemia (PMID: 21933854, 17968022), breast cancer (PMID: 19781682), and colon cancer (PMID: 27978560). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127403). Experimental studies have shown that this missense change causes reduced ATM kinase activity (PMID: 19431188). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000220146 SCV000272973 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Counsyl RCV000168297 SCV000800744 uncertain significance Ataxia-telangiectasia syndrome 2018-04-12 criteria provided, single submitter clinical testing
Color RCV000220146 SCV000904618 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000115208 SCV001143113 pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism.

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