ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.8151+2T>C

dbSNP: rs2136665852
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001975133 SCV002243316 pathogenic Ataxia-telangiectasia syndrome 2022-06-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ATM protein in which other variant(s) (p.Asp2708Asn) have been determined to be pathogenic (PMID: 16941484, 21665257, 21792198, 22071889, 23454770, 23632773, 27913932, 29909963). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 55, but is expected to preserve the integrity of the reading-frame (Invitae). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 55 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Ambry Genetics RCV004946941 SCV005515734 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-11 criteria provided, single submitter clinical testing The c.8151+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 54 in the ATM gene. 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. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). Based on the available evidence, the clinical significance of this alteration remains unclear.

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