ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.728T>C (p.Leu243Ser) (rs786202096)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164740 SCV000215412 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000476928 SCV000546853 uncertain significance Ataxia-telangiectasia syndrome 2016-12-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 243 of the ATM protein (p.Leu243Ser). The leucine residue is weakly conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 185337). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000479879 SCV000566091 uncertain significance not provided 2015-03-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.728T>C at the cDNA level, p.Leu243Ser (L243S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu243Ser 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 Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Leu243Ser occurs at a position that is conserved across mammals and is not located in a known functional domain (Tavtigian 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Leu243Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.

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