Submissions for variant NM_000051.4(ATM):c.4109+1G>T

dbSNP: rs879254034

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235964	SCV000293242	likely pathogenic	not provided	2020-04-15	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; Not observed in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378173	SCV001575684	likely pathogenic	Ataxia-telangiectasia syndrome	2022-07-12	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: 245985). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 27 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	RCV002321904	SCV002632447	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-10-23	criteria provided, single submitter	clinical testing	The c.4109+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 26 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 donor 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.
Illumina Laboratory Services, Illumina	RCV001378173	SCV002762712	likely pathogenic	Ataxia-telangiectasia syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The ATM c.4109+1G>T variant results in the substitution of a guanine within the consensus splice donor site with a thymine, which may result in splicing defects. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.4109+1G>T variant is classified as likely pathogenic for ataxia-telangiectasia.
Baylor Genetics	RCV003469183	SCV004212193	likely pathogenic	Familial cancer of breast	2022-10-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469183	SCV004933289	likely pathogenic	Familial cancer of breast	2024-01-23	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.