ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4394T>C (p.Leu1465Pro) (rs730881391)

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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 RCV000220574 SCV000274029 likely pathogenic Hereditary cancer-predisposing syndrome 2016-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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,Deficient protein function in appropriate functional assay(s)
GeneDx RCV000159765 SCV000209785 likely pathogenic not provided 2015-06-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.4394T>C at the cDNA level, p.Leu1465Pro (L1465P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). This variant has been observed in trans with a 5Â’ frameshift variant in one individual with ataxia-telangiectasia where low levels of ATM expression (1%) were observed (Izatt 1999). In addition, Barone et al. (2009) showed that ATM Leu1465Pro results in reduced protein expression and reduced kinase activity. ATM Leu1465Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Leu1465Pro occurs at a position that is highly conserved across species and is not located in a known functional domain (Travis 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider ATM Leu1465Pro to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000206187 SCV000694280 likely pathogenic Ataxia-telangiectasia syndrome 2015-10-30 criteria provided, single submitter clinical testing Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Leucine (L) with a medium size and hydrophobic Proline (P). 4/4 in silico tools predict damaging outcome for this substitution. Variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.00084% which does not exceed the maximal expected allele frequency of a disease causing ATM variant (0.4%). The variant was reported in one A-T patient (Izatt_EJHG_1999) who was compound heterozygote for the variant of interest and a potentially deleterious frameshift/truncating variant 1355delC; p.Thr452Asnfs indicating the variant to have a role in A-T pathology. Furthermore, Izatt_EJHG_1999 showed the variant to result in low level of ATM expression indicating that the L1465P missense mutation may lead to instability of the protein. Additionally, Barone_Hum Mutat_2009 reported the L1465P ATM variant to have reduced kinase activity toward its downstream targets providing an independent support for the pathogenicity of the variant. A clinical laboratory classifies variant as Likely Pathogenic via ClinVar (without evidence to independently evaluate) and HGMD lists variant with a classification of Disease Mutation. Considering all evidence, the variant is classified as Likely Pathogenic.
Invitae RCV000206187 SCV000261048 uncertain significance Ataxia-telangiectasia syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1465 of the ATM protein (p.Leu1465Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs730881391, ExAC 0.002%). This variant was reported in an individual affected with ataxia-telangiectasia and in an individual affected with gastric and esophageal cancer (PMID: 10234507, 26681312).  ClinVar contains an entry for this variant (Variation ID: 181996). Experimental studies have shown that this missense change results in a reduction of ATM protein stability and ATM kinase activity (PMID: 10234507, 19431188). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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