Submissions for variant NM_000051.4(ATM):c.8786+1G>T

gnomAD frequency: 0.00001  dbSNP: rs17174393

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164050	SCV000214657	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-28	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). In silico splice site analysis predicts that this alteration will weaken 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	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 60 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with a family history of breast cancer and ataxia-telangiectasia (PMID: 8659541, 8808599, 9463314, 10330348, 10817650, 10980530, 11298136, 21445571, 21459046, 21792198). ClinVar contains an entry for this variant (Variation ID: 184741). Studies have shown that disruption of this splice site results in skipping of exon 60 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 Diagnostics, LLC DBA Color Health	RCV000164050	SCV001353288	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-11-26	criteria provided, single submitter	clinical testing	This variant causes a G>T nucleotide substitution at the +1 position of intron 60 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001558979	SCV001781030	pathogenic	not provided	2022-05-18	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 (gnomAD); Observed in an individual with breast cancer (Feliubadal 2021); This variant is associated with the following publications: (PMID: 28152038, 34426522, 33280026)
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; http://gnomad.broadinstitute.org). 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).
Fulgent Genetics, Fulgent Genetics	RCV002485015	SCV002778861	likely pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-07-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467284	SCV004212248	likely pathogenic	Familial cancer of breast	2022-07-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467284	SCV004931506	likely pathogenic	Familial cancer of breast	2024-02-05	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.