Submissions for variant NM_000051.3(ATM):c.2569C>G (p.Leu857Val) (rs876659486)

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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	RCV000215421	SCV000276017	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-29	criteria provided, single submitter	clinical testing	Insufficient evidence
GeneDx	RCV000236914	SCV000293776	uncertain significance	not provided	2015-12-28	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.2569C>G at the cDNA level, p.Leu857Val (L857V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu857Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Leu857Val occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). 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 Leu857Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color	RCV000215421	SCV001356365	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-17	criteria provided, single submitter	clinical testing
Invitae	RCV001221171	SCV001393197	uncertain significance	Ataxia-telangiectasia syndrome	2019-04-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 857 of the ATM protein (p.Leu857Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 232001). 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 valine 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 and their clinical significance is uncertain. 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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