Submissions for variant NM_000051.4(ATM):c.8987+1G>C

dbSNP: rs786203631

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167026	SCV000217849	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-07	criteria provided, single submitter	clinical testing	The c.8987+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after exon 61 of the ATM gene. This alteration has been detected in conjunction with a truncating ATM mutation in an individual with ataxia-telangiectasia (Buzin CH, Hum. Mutat. 2003 Feb; 21(2):123-31). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation.
Invitae	RCV003500511	SCV004307934	pathogenic	Ataxia-telangiectasia syndrome	2023-05-29	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.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 10980530, 18560558, 19691550, 26628246). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in activation of a cryptic splice site (Invitae). ClinVar contains an entry for this variant (Variation ID: 187308). 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 62 of the ATM gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Myriad Genetics, Inc.	RCV004019994	SCV004931940	likely pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.