ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2942G>A (p.Arg981His) (rs755896387)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221720 SCV000274390 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000469446 SCV000546663 uncertain significance Ataxia-telangiectasia syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 981 of the ATM protein (p.Arg981His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs755896387, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 230737). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". The histidine 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 RCV000587251 SCV000566732 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.2942G>A at the cDNA level, p.Arg981His (R981H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been reported in 1/13,087 breast cancer cases and 0/5,488 controls (Decker 2017). ATM Arg981His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (Tavtigian 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Arg981His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000221720 SCV000687435 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175361 SCV000694241 uncertain significance not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: ATM c.2942G>A (p.Arg981His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250702 control chromosomes. 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.2942G>A in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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