ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1047G>A (p.Met349Ile) (rs768480943)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000579935 SCV000681950 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing
GeneDx RCV000235762 SCV000292904 uncertain significance not provided 2016-03-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.1047G>A at the cDNA level, p.Met349Ile (M349I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Met349Ile 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 Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Met349Ile occurs at a position where amino acids with properties similar to Methionine are tolerated 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 Met349Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000471228 SCV000546801 uncertain significance Ataxia-telangiectasia syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 349 of the ATM protein (p.Met349Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs768480943, ExAC 0.03%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 245781). 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.

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