ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7181C>T (p.Ser2394Leu) (rs587779861)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115242 SCV000149151 likely pathogenic not provided 2018-04-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.7181C>T at the cDNA level, p.Ser2394Leu (S2394L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant was reported in trans with a pathogenic ATM variant in a patient with Ataxia-Telangiectasia, and a cell-line derived from this patient demonstrated little or no kinase activity against Chk2 (Lin 2015). Additionally, ATM Ser2394Leu was shown in an in-vitro expression system to have no kinase activity on multiple downstream targets and limited autophosphorylation (Austen 2008, Barone 2009). ATM Ser2394Leu was not observed in large population cohorts (Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ser2394Leu occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider ATM Ser2394Leu to be a likely pathogenic variant.
Ambry Genetics RCV000494662 SCV000581469 likely pathogenic Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification
Invitae RCV000534806 SCV000622719 likely pathogenic Ataxia-telangiectasia syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2394 of the ATM protein (p.Ser2394Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with ataxia-telangiectasia (PMID: 26677768). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 127437). Experimental studies have shown that this missense change results in the loss of ATM kinase activity (PMID: 18573109, 19431188). Also, a cell line derived from an affected individual carrying this variant in compound heterozygosity with the c.1564delGA truncating variant showed reduced ATM expression, X-irradiation (XR)-induced phosphorylated CHEK2 expression, and XR-induced gamma H2A.X nuclear puncta compared to wild-type cell lines (PMID: 26677768). 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.

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