ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4792C>A (p.Leu1598Ile) (rs375190373)

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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 RCV000159729 SCV000218080 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000159729 SCV000682223 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515276 SCV000611365 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000212024 SCV000209742 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.4792C>A at the cDNA level, p.Leu1598Ile (L1598I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1598Ile was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1598Ile occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Leu1598Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000198328 SCV000254115 uncertain significance Ataxia-telangiectasia syndrome 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 1598 of the ATM protein (p.Leu1598Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs375190373, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181962). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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