ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7307G>A (p.Arg2436Lys) (rs786203394)

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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 RCV000166679 SCV000217487 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-29 criteria provided, single submitter clinical testing The c.7307G>A variant (also known as p.R2436K), located in coding exon 48 of the ATM gene, results from a G to A substitution at nucleotide position 7307. The amino acid change results in arginine to lysine at codon 2436, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 48, which makes it likely to have some effect on normal mRNA splicing. Internal RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000230377 SCV000283045 uncertain significance Ataxia-telangiectasia syndrome 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 2436 of the ATM protein (p.Arg2436Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 49 of the ATM coding sequence, which is part of the consensus splice site for this exon. 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: 187003). 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 disruptive, 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.
Color Health, Inc RCV000166679 SCV001339681 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-23 criteria provided, single submitter clinical testing
Natera, Inc. RCV000230377 SCV001458465 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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