Submissions for variant NM_000051.3(ATM):c.361T>A (p.Leu121Ile) (rs587782178)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130797	SCV000185692	uncertain significance	Hereditary cancer-predisposing syndrome	2013-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000235623	SCV000293542	uncertain significance	not provided	2015-11-12	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.361T>A at the cDNA level, p.Leu121Ile (L121I) at the protein level, and results in the change of a Leucine to an Isoleucine (TTA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu121Ile 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 Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Leu121Ile occurs at a position that is conserved 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 Leu121Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000463681	SCV000546917	uncertain significance	Ataxia-telangiectasia syndrome	2018-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with isoleucine at codon 121 of the ATM protein (p.Leu121Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 142013). 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: "Tolerated"; PolyPhen-2: "Probably 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.