ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5177+5G>A

dbSNP: rs759373136
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000673901 SCV000822473 likely pathogenic Ataxia-telangiectasia syndrome 2021-11-19 criteria provided, single submitter clinical testing Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 34 and introduces a premature termination codon (PMID: 23143971). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 557726). This variant has been observed in individual(s) with ataxia-telangiectasia and/or isolated segmental dystonia (PMID: 23143971, 33098801). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs759373136, gnomAD 0.0009%). This sequence change falls in intron 34 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. 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 Diagnostics, LLC DBA Color Health RCV000777914 SCV000913952 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-25 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +5 position of intron 34 splice donor site of the ATM gene. This variant has been reported in a 41 year-old individual affected with mild form of ataxia telangiectasia in compound heterozygous state with a pathogenic truncation variant (PMID: 23143971). An RT-PCR analysis using cellular RNA derived from the proband has shown that this variant disrupts RNA splicing and causes an out-of-frame skipping of exon 34 (PMID: 23143971). There was no detectable ATM protein expression or kinase activity in the cells from the proband (PMID: 23143971). This variant has been identified in 1/250868 chromosomes 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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000673901 SCV001150021 pathogenic Ataxia-telangiectasia syndrome 2018-01-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000777914 SCV002641399 pathogenic Hereditary cancer-predisposing syndrome 2021-06-15 criteria provided, single submitter clinical testing The c.5177+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 33 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was reported in conjunction with a pathogenic ATM mutation in a patient with ataxia-telangiectasia (Worth PF et al. Mov Disord, 2013 Apr;28:524-8). 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.
Baylor Genetics RCV003459643 SCV004213953 likely pathogenic Familial cancer of breast 2021-11-24 criteria provided, single submitter clinical testing
Counsyl RCV000673901 SCV000799155 uncertain significance Ataxia-telangiectasia syndrome 2018-04-05 flagged submission clinical testing
Natera, Inc. RCV000673901 SCV002080861 likely pathogenic Ataxia-telangiectasia syndrome 2021-09-24 no assertion criteria provided clinical testing

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