ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5176T>G (p.Cys1726Gly)

gnomAD frequency: 0.00001  dbSNP: rs770882126
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001040691 SCV001204280 uncertain significance Ataxia-telangiectasia syndrome 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1726 of the ATM protein (p.Cys1726Gly). This variant is present in population databases (rs770882126, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 839024). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Color Diagnostics, LLC DBA Color Health RCV001180026 SCV001344863 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-15 criteria provided, single submitter clinical testing This missense variant replaces cysteine with glycine at codon 1726 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV002260677 SCV002540283 uncertain significance not provided 2022-07-01 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in 0/646 individuals with leukemia and in 1/8920 unaffected controls (Tiao 2017); This variant is associated with the following publications: (PMID: 28652578)
Ambry Genetics RCV001180026 SCV002643123 likely benign Hereditary cancer-predisposing syndrome 2023-12-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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