ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5362G>A (p.Gly1788Ser) (rs730881373)

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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 RCV000223069 SCV000278292 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000223069 SCV000903675 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000159732 SCV000209746 uncertain significance not provided 2016-11-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.5362G>A at the cDNA level, p.Gly1788Ser (G1788S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). ATM Gly1788Ser has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a colorectal cancer tumor and a stomach carcinoma (Li-Chang 2015, Yu 2015). ATM Gly1788Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Gly1788Ser occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Gly1788Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000542658 SCV000622582 uncertain significance Ataxia-telangiectasia syndrome 2017-11-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1788 of the ATM protein (p.Gly1788Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs730881373, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181965). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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