Submissions for variant NM_000051.4(ATM):c.7307+1G>A

dbSNP: rs2086003529

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377732	SCV001575133	likely pathogenic	Ataxia-telangiectasia syndrome	2022-11-28	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1066672). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 15880721). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 49 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Ambry Genetics	RCV002384543	SCV002669716	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-20	criteria provided, single submitter	clinical testing	The c.7307+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 48 of the ATM gene. This alteration has been identified in the compound heterozygous state with a second ATM mutation in an individual diagnosed with ataxia-telangiectasia (AT) (Birrell GW et al. Hum. Mutat., 2005 Jun;25:593). 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). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003469630	SCV004210149	pathogenic	Familial cancer of breast	2023-07-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469630	SCV004933310	likely pathogenic	Familial cancer of breast	2024-01-31	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.