Submissions for variant NM_000051.4(ATM):c.5178-1G>A

dbSNP: rs1555105579

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674911	SCV000800323	likely pathogenic	Ataxia-telangiectasia syndrome	2018-05-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001023662	SCV001185574	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-12-10	criteria provided, single submitter	clinical testing	The c.5178-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 34 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000674911	SCV001575746	pathogenic	Ataxia-telangiectasia syndrome	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 34 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of ataxia-telangiectasia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558613). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000674911	SCV003841362	pathogenic	Ataxia-telangiectasia syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000558613). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000674911	SCV004238482	likely pathogenic	Ataxia-telangiectasia syndrome	2023-04-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004026138	SCV004932042	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.