Submissions for variant NM_000051.4(ATM):c.5496+2_5496+5del

dbSNP: rs1565479572

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000685410	SCV000812889	likely pathogenic	Ataxia-telangiectasia syndrome	2022-06-27	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: 565770). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 21665257). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 36 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).
Color Diagnostics, LLC DBA Color Health	RCV001191641	SCV001359534	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-12-02	criteria provided, single submitter	clinical testing	This variant causes 4 nucleotides deletion at the +2 position in intron 36 of the ATM gene. Splice site prediction tools predict 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. 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	RCV001191641	SCV002652715	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	The c.5496+2_5496+5delTAAG variant results from a deletion of 4 nucleotides between positions c.5496+2 and 5496+5 and involves the canonical splice donor site after coding exon 35 of the ATM gene. This alteration has been reported in one patient with ataxia telangiectasia (Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). The canonical splice donor site is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Fulgent Genetics, Fulgent Genetics	RCV002485586	SCV002795232	likely pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-12-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003465555	SCV004212215	likely pathogenic	Familial cancer of breast	2022-09-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003465555	SCV004933201	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.