ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.633C>G (p.Asp211Glu) (rs1060501634)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461974 SCV000546937 uncertain significance Ataxia-telangiectasia syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 211 of the ATM protein (p.Asp211Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 407613). 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 glutamic acid 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.
GeneDx RCV000482340 SCV000570706 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.633C>G at the cDNA level, p.Asp211Glu (D211E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asp211Glu 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 Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. ATM Asp211Glu occurs at a position that is not conserved and is not located in a known functional domain (Stracker 2013, Tavtigian 2009). 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 Asp211Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572097 SCV000667867 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-12 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV001174925 SCV001338364 uncertain significance not specified 2020-02-17 criteria provided, single submitter clinical testing Variant summary: ATM c.633C>G (p.Asp211Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251182 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.633C>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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