Submissions for variant NM_000051.4(ATM):c.8584+2T>C

gnomAD frequency: 0.00001  dbSNP: rs730881326

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411372	SCV000487007	likely pathogenic	Ataxia-telangiectasia syndrome	2016-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567828	SCV000660716	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	clinical testing	The c.8584+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 57 in the ATM gene. This alteration was seen in a proband with ataxia telangiectasia who presented with ataxia, gross motor delay, and neutropenia. This individual was compound heterozygous for another pathogenic mutation in the ATM gene. RT-PCR demonstrated that c.8584+2T>C results in an abnormally spliced transcript that is subject to nonsense mediated mRNA decay (Balci TB et al. Clin. Genet. 2017 Sep;92(3):281-289). This alteration was also seen in a patient with familial colorectal cancer (Hansen MF et al. Clin. Genet. 2017 Oct;92(4):405-414). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
NxGen MDx	RCV000567828	SCV001548250	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-19	criteria provided, single submitter	clinical testing	This SNV (c.8584+2T>C) is predicted to disrupt a canonical splice site (PVS1). This variant is not found in genomAD exomes or genomes (PM2). Pathogenic computational predictions have been made based on computer algorithms with no conflicting benign verdicts (PP3). This variant has been observed in Hansen et al. PMID 28195393 where it was classified as pathogenic. We interpret c.8584+2T>C to be likely pathogenic.
Invitae	RCV000411372	SCV001587042	pathogenic	Ataxia-telangiectasia syndrome	2023-01-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 28170084). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 181899). Disruption of this splice site has been observed in individual(s) with clinical features of ataxia-telangiectasia, and in individual(s) with colorectal cancer (PMID: 28170084, 28195393; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 58 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798543	SCV002042305	likely pathogenic	Breast and/or ovarian cancer	2020-04-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462070	SCV004213946	pathogenic	Familial cancer of breast	2021-12-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000567828	SCV004361915	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 58 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been observed in the compound heterozygous state in an individual affected with ataxia-telangiectasia (PMID: 28170084). RT-PCR of samples from this individual showed an alternative splice product lacking 19 nucleotides in exon 58 which leads to nonsense-mediated mRNA decay. This variant has also been observed in an individual with a personal and family history of colorectal cancer (PMID: 28195393). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.