Submissions for variant NM_000051.4(ATM):c.5497-2A>G

dbSNP: rs786203796

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167256	SCV000218097	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The c.5497-2A>G pathogenic mutation results from an A to G substitution two nucleotides before coding exon 36 of the ATM gene. An alteration impacting the same nucleotide position has been reported in a patient with ataxia-telangiectasia (AT) (Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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.
Color Diagnostics, LLC DBA Color Health	RCV000167256	SCV000687624	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-25	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 36 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. To our knowledge, 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627890	SCV000748774	pathogenic	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 36 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 individual(s) with ataxia-telangiectasia (PMID: 10330348). ClinVar contains an entry for this variant (Variation ID: 187521). Studies have shown that disruption of this splice site results in activation of a cryptic splice site 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.
Baylor Genetics	RCV003468802	SCV004212171	likely pathogenic	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468802	SCV004930944	likely pathogenic	Familial cancer of breast	2024-01-25	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.
Department of Human Genetics, Hannover Medical School	RCV003468802	SCV005061711	pathogenic	Familial cancer of breast	2024-06-21	criteria provided, single submitter	clinical testing
GeneDx	RCV004719730	SCV005325874	pathogenic	not provided	2024-01-22	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); Also known as IVS38-2A>G; This variant is associated with the following publications: (PMID: 27159176)