ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6199-2A>T (rs1060501570)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475818 SCV000546753 likely pathogenic Ataxia-telangiectasia syndrome 2016-04-09 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 42 of the ATM gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in ATM are known to be pathogenic (PMID: 10817650, 19781682). A different variant at the canonical acceptor splice site of intron 42, c.6199-1G>T (also known as 6199del9 and IVS41-1G>T), has been reported in a heterozygous individual with pancreatic cancer (PMID: 22585167), and a homozygous individual with ataxia-telangiectasia (PMID: 9450906). Experimental studies have shown that the c.6199-1G>T variant abolishes the canonical acceptor site, leading to the utilization of a cryptic splice site 9 nucleotides downstream, and the subsequent in-frame deletion of the first three amino acids of exon 43 (PMID: 9450906). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this c.6199-2A>T variant may lead to a similar loss of the canonical acceptor splice site and utilization of the downstream cryptic splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in ATM are known to be pathogenic. However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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