ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2849T>G (p.Leu950Arg) (rs786203054)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166191 SCV000216968 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000255989 SCV000321411 likely pathogenic not provided 2017-11-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.2849T>G at the cDNA level, p.Leu950Arg (L950R) at the protein level, and results in the change of a Leucine to an Arginine (CTT>CGT). This variant, also published as ATM L949R, has been observed in multiple individuals with Ataxia-Telangiectasia (A-T) and functional studies on lymphoblastoid cell lines report associations with low ATM protein, reduced to undetectable kinase activity, and increased IR-induced chromosomal aberrations (ICA) count (Becker-Catania 2000, Buzin 2003, Thompson 2005, Fang 2010, Reiman 2011). In addition, this variant has been identified in at least two individuals with prostate cancer (Na 2016, Mandelker 2017). ATM Leu950Arg was not observed in large population cohorts (Lek 2016). Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Leu950Arg is located in the beta-adaptin interaction domain (Tavtigian 2009). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, we consider ATM Leu950Arg to be a likely pathogenic variant.
Invitae RCV000628016 SCV000748903 likely pathogenic Ataxia-telangiectasia syndrome 2019-10-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 950 of the ATM protein (p.Leu950Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with ataxia-telangiectasia (PMID: 10873394, 20678261, 12552559, 21792198) and in the heterozygous state in an individual with pancreatic cancer (PMID: 27989354). This variant is also known in the literature as L949R. ClinVar contains an entry for this variant (Variation ID: 186574). Experimental studies have shown that patient-derived cells containing this variant have reduced ATM protein levels and kinase activity, and increased amount of IR-induced chromosomal aberrations when compared with wild-type cells (PMID: 20678261, 10873394). 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.
Color RCV000166191 SCV000913907 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-23 criteria provided, single submitter clinical testing

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