ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8786+1G>T (rs17174393)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164050 SCV000214657 pathogenic Hereditary cancer-predisposing syndrome 2019-11-15 criteria provided, single submitter clinical testing The c.8786+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 59 of the ATM gene. To our knowledge, this alteration has not been reported in published literature to date; however, a different nucleotide change at the same position, c.8786+1G>A (also known as IVS62+1G>A), has been detected in numerous ataxia-telangiectasia kindreds (Stankovic T et al. Am J Hum Genet. 1998 Feb;62(2):334-45; Laake K et al. Hum Mutat. 2000 Sep;16(3):232-46; Li A and Swift M. Am J Med Genet. 2000 May 29;92(3):170-7). Based on two different splice site prediction tools, the c.8786+1G>T alteration is expected to abolish 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000540315 SCV000622851 pathogenic Ataxia-telangiectasia syndrome 2019-12-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 60 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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 disease. ClinVar contains an entry for this variant (Variation ID: 184741). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). Two different variants affecting this nucleotide (c.8786+1G>A, c.8786+1G>C) have been reported in individuals affected with ataxia telangiectasia and breast cancer (PMID: 8808599, 10330348, 8659541, 10980530, 9463314, 11298136, 10817650, 21459046, 21792198, 21445571, invitae database), and have been determined to be pathogenic, indicating that this nucleotide may be crucial for normal RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000540315 SCV000792812 likely pathogenic Ataxia-telangiectasia syndrome 2017-07-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164050 SCV001353288 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-26 criteria provided, single submitter clinical testing
GeneDx RCV001558979 SCV001781030 pathogenic not provided 2019-04-30 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28152038)
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000164050 SCV001911491 pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.8786+1G>T variant is located in the canonical donor splice site of intron 60 and it is predicted to cause the skipping of exon 60 and the disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; Semiquantitative splicing analysis shows a 55% of altered band and 45% of wild type band after RT-PCR of puromycin-cultured lymphocyte carrier RNA. The altered band is the result of the predicted skipping of exon 60 (PS3_Moderate; M. Santamariña and A. Vega., unpublished data). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS3_Moderate (PMID: 33280026).

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