ClinVar Miner

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

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166679 SCV000217487 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000230377 SCV000283045 uncertain significance Ataxia-telangiectasia syndrome 2015-12-22 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. It also falls at the last base of exon 49 of the ATM coding sequence. This variant affects a highly conserved nucleotide within the consensus splice site of exon 49. The majority of exons (75-85%) have a G at this position (PMID: 9536098). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 187003). Nucleotide substitutions at last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In addition, 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. In summary, this is a novel missense change with uncertain impact on protein function and splicing. It has been classified as a Variant of Uncertain Significance.

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