ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.496+5G>A (rs796051858)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213739 SCV000273575 likely pathogenic Hereditary cancer-predisposing syndrome 2017-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000235952 SCV000293428 likely pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.496+5G>A or IVS5+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 5 of the ATM gene. Multiple in silico models predict this variant to destroy the nearby natural donor site, and to possibly cause abnormal gene splicing. This variant, also published as IVS7+5G>A using alternate exon numbering, has been observed in the compound heterozygous state in at least two individuals diagnosed with an attenuated form of Ataxia Telangiectasia (Dork 2004, Verhagen 2009). Dork et al. (2004) found the cell line of one of these patients, who also harbored two ATM missense variants, to exhibit modest levels of chromosomal instability, a reduction of ATM protein compared to wild type and skipping of exon 5 (corresponding to Dork's published exon 7), ATM c.496+5G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. Based on currently available information and internal data, we consider ATM c.496+5G>A to be a likely pathogenic variant.
Invitae RCV000558736 SCV000622549 likely pathogenic Ataxia-telangiectasia syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals with an attenuated form of ataxia-telangiectasia (PMID: 15054841, 19535770). ClinVar contains an entry for this variant (Variation ID: 3047) Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies using patient lymphoblastoid cells have shown that this variant causes a splicing defect and leads to a reduced cellular response to irradiation (PMID: 15054841). 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.
Color RCV000213739 SCV000687588 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing
Counsyl RCV000558736 SCV000797382 likely pathogenic Ataxia-telangiectasia syndrome 2018-02-01 criteria provided, single submitter clinical testing
OMIM RCV000003188 SCV000023346 pathogenic Ataxia-telangiectasia variant 2004-04-30 no assertion criteria provided literature only

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