Submissions for variant NM_000051.4(ATM):c.3993+1G>T

dbSNP: rs200196781

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409640	SCV000486393	likely pathogenic	Ataxia-telangiectasia syndrome	2016-05-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409640	SCV002210640	pathogenic	Ataxia-telangiectasia syndrome	2021-05-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. Disruption of this splice site has been observed in individual(s) with with ataxia-telangiectasia (PMID: 10980530, 12815592). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 370954). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 26 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	RCV002374612	SCV002625015	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-27	criteria provided, single submitter	clinical testing	The c.3993+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 25 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 and will result in the creation or strengthening of a novel 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site (c.3993+1G>A ), has been shown to have a similar impact on splicing (Ambry internal data) and has has been described in several ataxia-telangiectasia families (Laake K et al. Hum. Mutat. 2000; 16:232-46; Mitui M et al. Hum. Mutat. 2003; 22:43-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003470339	SCV004212204	likely pathogenic	Familial cancer of breast	2022-10-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003470339	SCV004932328	pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing	This variant is considered 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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12815592, 21665257, 10980530]. Functional studies indicate this variant impacts protein function [PMID: 12815592, 21665257, 10980530].
GeneDx	RCV004591138	SCV005080002	pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25614872, 23807571, 12815592, 10980530)