Submissions for variant NM_000051.4(ATM):c.495_496+16del

dbSNP: rs1555059522

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000576471	SCV000678183	likely pathogenic	Ataxia-telangiectasia syndrome	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576471	SCV001221141	likely pathogenic	Ataxia-telangiectasia syndrome	2022-05-29	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: 487452). 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 variant results in the deletion of part of exon 5 (c.495_496+16del) 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	RCV001191912	SCV001359847	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	This variant deletes 18 nucleotides at the exon 5/intron 5 splice junction 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 a disrupted protein product. To our knowledge, 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Sema4, Sema4	RCV001191912	SCV002527701	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	curation
Ambry Genetics	RCV001191912	SCV002642595	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	clinical testing	The c.495_496+16del18 pathogenic mutation results from a deletion of 18 nucleotides between positions c.495 and c.496+16 and involves the canonical splice donor site after coding exon 4 of the ATM gene. 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. 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.496+5G>A) has been shown to have a similar impact on splicing and has been reported in ataxia-telangiectasia (A-T) patients (Dörk T et al. Am. J. Med. Genet. 2004 Apr;126A(3):272-7; Verhagen MM et al. Neurology 2009 Aug;73(6):430-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004024585	SCV004930556	likely pathogenic	Familial cancer of breast	2024-01-10	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.
Natera, Inc.	RCV000576471	SCV002093952	likely pathogenic	Ataxia-telangiectasia syndrome	2021-02-07	no assertion criteria provided	clinical testing