Submissions for variant NM_000051.4(ATM):c.4611+1del

dbSNP: rs1565461824

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000777457	SCV000913319	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-07-22	criteria provided, single submitter	clinical testing	This variant deletes a nucleotide at the +1 position of intron 30 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV000777457	SCV002637764	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-06-14	criteria provided, single submitter	clinical testing	The c.4611+1delG intronic variant, located in intron 29 of the ATM gene, results from a deletion of one nucleotide within intron 29 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002536722	SCV003314278	likely pathogenic	Ataxia-telangiectasia syndrome	2022-03-28	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 30 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). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 631284). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Myriad Genetics, Inc.	RCV004027305	SCV004930751	likely pathogenic	Familial cancer of breast	2024-03-29	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.