ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7926A>C (p.Arg2642Ser) (rs863224440)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197870 SCV000253671 likely pathogenic Ataxia-telangiectasia syndrome 2015-03-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 2642 of the ATM protein (p.Arg2642Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases. It has been reported in an individual with ataxia-telangiectasia (A-T), who had a pathogenic truncating variant (p.Arg2443*) on the opposite chromosome (PMID: 8808599; http://chromium.liacs.nl/LOVD2/variants.php?select_db=ATM&action=view&view=0002110%2C0000192%2C1). This variant is located 2 nucleotides from the end of exon 53 and affects a highly conserved nucleotide within the consensus donor splice site for this exon. The majority of exons (~60%) have an A at this position (PMID: 9536098). Experimental studies demonstrate that this variant disrupts splicing and leads to the deletion of either exons 52 and 53 together or exon 53 alone from the ATM mRNA (PMID: 8808599). In summary, this variant is not seen in the general population, has been observed in trans with a truncating mutation in a patient with ataxia-telangiectasia, and is reported to disrupt splicing of the ATM mRNA. For these reasons , this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000215938 SCV000278004 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000420030 SCV000520897 likely pathogenic not provided 2018-01-08 criteria provided, single submitter clinical testing The R2642S variant has been detected in a cell line derived from a patient with ataxia-telangiectasia, along with two nonsense variants in the ATM gene (Wright et al., 1996). However, it is unknown whether the variant was a somatic change or was present in the germline. The variant 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. The R2642S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Several in-silico splice prediction models predict that R2642S may damage the natural splice donor site in intron 53 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence changel is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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