Submissions for variant NM_000051.4(ATM):c.5319+2T>C

dbSNP: rs1555105842

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565533	SCV000660641	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-21	criteria provided, single submitter	clinical testing	The c.5319+2T>C pathogenic mutation results from a T to C substitution two nucleotides after coding exon 35 of the ATM gene. This alteration has been previously reported (designated as IVS37+2T>C) in a compound heterozygous individual with A-T (with ATM c.5692C>T) (Magliozzi M et al. Dis. Markers. 2006 ;22(4):257-64, Prodosmo A et al.J. Clin. Invest. 2013 Mar;123(3):1335-42). Further, western blot analysis showed no detectable ATM protein, and functional studies on lymphoblastoid cell lines showed a significant decrease in the percentage of mitotic cells with p53 localization at the centrosome, which is directly dependent on ATM function (Prodosmo A et al.J. Clin. Invest. 2013 Mar;123(3):1335-42). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801687	SCV000941477	likely pathogenic	Ataxia-telangiectasia syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 35 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). Disruption of this splice site has been observed in individual(s) with ataxia telangiectasia (PMID: 17124347, 23454770). ClinVar contains an entry for this variant (Variation ID: 479006). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 23454770). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000801687	SCV001360416	likely pathogenic	Ataxia-telangiectasia syndrome	2019-03-01	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5319+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245606 control chromosomes (gnomAD). c.5319+2T>C has been reported in the literature in heterozygous state with another pathogenic variant (ATM 5692C>T, R1898X), in an individual affected with Ataxia-Telangiectasia (Magliozzi_2006). Protein expression analysis carried out on cells derived from the patient showed zero ATM protein level (Prodosmo_2013). The variant has also been detected in one breast cancer patient (Hauke_2018). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002060383	SCV002496218	pathogenic	not provided	2022-03-11	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; Observed with a pathogenic variant apparently on the opposite allele (in trans) in a patient with classical ataxia telangiectasia syndrome and absent ATM protein expression in published literature (Gilad 1996, Magliozzi 2006, Menotta 2012); Observed in individuals with a personal or family history including breast cancer (Hauke 2016); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS37+2T>C; This variant is associated with the following publications: (PMID: 29522266, 17124347, 8845835, 23055520)
AiLife Diagnostics, AiLife Diagnostics	RCV002060383	SCV002502133	likely pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003155950	SCV004207091	pathogenic	Familial cancer of breast	2023-11-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000565533	SCV004361736	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 35 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 (also known as IVS37+2T>C in the literature) has been reported in the compound heterozygous state with an additional pathogenic ATM variant in an individual affected with ataxia telangiectasia (PMID: 17124347, 23454770). It has been reported that cells derived from this individual had no detectable ATM protein (PMID: 23454770). This variant has also been reported in at least one individual affected with breast cancer (PMID: 29522266). 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.
Myriad Genetics, Inc.	RCV003155950	SCV004932453	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.
BRCAlab, Lund University	RCV003155950	SCV002588911	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing