Submissions for variant NM_000051.4(ATM):c.5005+1G>T

gnomAD frequency: 0.00001  dbSNP: rs1057517427

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412271	SCV000487268	likely pathogenic	Ataxia-telangiectasia syndrome	2016-11-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001023407	SCV001185276	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	The c.5005+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 32 of the ATM gene. This variant was identified in conjunction with a pathogenic variant in ATM in one individual from the UK diagnosed with ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol, 2016 Jul;58:690-7). This alteration has also been reported in a patient with pancreatic cancer (Yu Y et al. HGG Adv, 2022 Jan;3:100078). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412271	SCV001382047	likely pathogenic	Ataxia-telangiectasia syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 33 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened 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 ATM-related conditions (PMID: 26896183, 35047863). ClinVar contains an entry for this variant (Variation ID: 371636). Studies have shown that disruption of this splice site results in skipping of exon 33, but is expected to preserve the integrity of the reading-frame (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001023407	SCV001735473	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-28	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 33 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. 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). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003463809	SCV004207069	uncertain significance	Familial cancer of breast	2023-10-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003463809	SCV004931712	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.
GeneDx	RCV004719808	SCV005325997	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Identified with a second ATM variant, phase unknown, in an individual reported to have ataxia-telangiectasia (PMID: 26896183); Observed in an individual with pancreatic cancer (PMID: 35047863); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35047863, 26896183)