ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.8151G>A (p.Lys2717=) (rs1591192550)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001027230 SCV001189748 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-01 criteria provided, single submitter clinical testing The c.8151G>A variant (also known as p.K2717K), located in coding exon 54 of the ATM gene, results from a G to A substitution at nucleotide position 8151. This nucleotide substitution does not change the amino acid at codon 2717. However, this change occurs in the last base pair of coding exon 54, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001027230 SCV001342031 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-19 criteria provided, single submitter clinical testing
Invitae RCV001207545 SCV001378905 uncertain significance Ataxia-telangiectasia syndrome 2019-10-20 criteria provided, single submitter clinical testing This sequence change affects codon 2717 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. This variant also falls at the last nucleotide of exon 55 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. 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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