Submissions for variant NM_000051.4(ATM):c.185+1G>A

dbSNP: rs112805604

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205116	SCV000260525	likely pathogenic	Ataxia-telangiectasia syndrome	2021-10-16	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. Donor and acceptor splice site variants 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ATM-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV002408894	SCV002715168	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-27	criteria provided, single submitter	clinical testing	The c.185+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the ATM gene. 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. 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 likely pathogenic.
Baylor Genetics	RCV003468943	SCV004212070	likely pathogenic	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468943	SCV004932480	likely pathogenic	Familial cancer of breast	2024-01-08	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.