ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5674G>A (p.Glu1892Lys) (rs730881375)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000771875 SCV000904623 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000159736 SCV000209750 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.5674G>A at the cDNA level, p.Glu1892Lys (E1892K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Glu1892Lys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. The nucleotide which is altered, a guanine (G) at base 5674, is conserved across species and is not located in a known functional domain. While protein function based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may destroy the natural splice donor site for intron 37 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether ATM Glu1892K is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000694433 SCV000822879 uncertain significance Ataxia-telangiectasia syndrome 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1892 of the ATM protein (p.Glu1892Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant also falls at the last nucleotide of exon 37 of the ATM coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs730881375, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181969). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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