ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7664A>G (p.His2555Arg)

gnomAD frequency: 0.00001  dbSNP: rs876658925
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214254 SCV000274780 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-14 criteria provided, single submitter clinical testing The p.H2555R variant (also known as c.7664A>G), located in coding exon 51 of the ATM gene, results from an A to G substitution at nucleotide position 7664. The histidine at codon 2555 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in a patient with ataxia telangiectasia (AT) who was also found to be positive for a truncating alteration in ATM that was classified as pathogenic; however, the phase (cis vs trans) of these two alterations was not determined (Kumar KR et al. Parkinsonism Relat Disord, 2019 12;69:111-118). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000214254 SCV000913995 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001222431 SCV001394529 uncertain significance Ataxia-telangiectasia syndrome 2024-10-23 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2555 of the ATM protein (p.His2555Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 31731261). ClinVar contains an entry for this variant (Variation ID: 231049). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001770175 SCV002003143 uncertain significance not provided 2020-12-11 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with a pathogenic variant in an individual with features suggestive of ataxia telangiectasia but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Kumar 2019); This variant is associated with the following publications: (PMID: 31731261)

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