ClinVar Miner

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

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Total submissions: 7
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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 2019-06-14 criteria provided, single submitter clinical testing 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 2019-12-26 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 2019-11-14 criteria provided, single submitter clinical testing
Counsyl RCV000558736 SCV000797382 likely pathogenic Ataxia-telangiectasia syndrome 2018-02-01 criteria provided, single submitter clinical testing
Pittsburgh Clinical Genomics Laboratory,University of Pittsburgh Medical Center RCV001249854 SCV001424016 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-20 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (G>A) that occurs at the +5 position of intron 5 of the ATM gene. This variant has not been observed in the Exome Aggregation Consortium (ExAC) database. RNA analysis indicates that c.496+5G>A causes a splicing defect leading to an in-frame deletion of exon 5 (identified in the publication as exon 7), shortening the RNA by 165 nucleotides (PMID: 15054841) and the protein by 55 amino acid residues (p.Arg111_Glu166del55insLys). This shortened protein deriving from the variant has a decrease to only 20-40% of the expression of a wild-type variant, and cells had markedly reduced phosphorylation activity toward p53 and NBS1/p95 after radiation exposure (PMID: 15054841). ATM:c.496+5G>A is found in the case described in this paper, as well as two unrelated families affected by ataxia-telangiectasia (A-T). In the two documented cases of A-T where the variant was present, it was also found to be compound heterozygous with known pathogenic variant c.7875_7876delTGinsGC (p.Asp2625_Ala2626delinsGluPro). Despite the clear association of ATM:c.496+5G>A with risk for A-T, its association with hereditary cancer is less clear. Based on these data, we consider this variant to be likely pathogenic.
OMIM RCV000003188 SCV000023346 pathogenic Ataxia-telangiectasia variant 2004-04-30 no assertion criteria provided literature only

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