Submissions for variant NM_000051.3(ATM):c.4323A>G (p.Ile1441Met) (rs587779839)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115189	SCV000149098	uncertain significance	not provided	2014-03-18	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4323A>G at the cDNA level, p.Ile1441Met (I1441M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile1441Met 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 Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution and is unlikely to affect protein integrity. ATM Ile1441Met occurs at a position that is moderately conserved across species and is not located in a known functional domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Ile1441Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000685464	SCV000812946	uncertain significance	Ataxia-telangiectasia syndrome	2018-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with methionine at codon 1441 of the ATM protein (p.Ile1441Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. 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: 127384). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Color	RCV000777909	SCV000913941	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-07	criteria provided, single submitter	clinical testing

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