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 2017-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000221720 SCV000687435 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000587251 SCV000694241 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The ATM c.2942G>A (p.Arg981His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution within the Armadillo-like helical and fold domain (InterPro). 1/2 in silico tools predict a damaging outcome for this variant (MutationTaster and SNPs&GO not captured due to low p-value and reliability index, respectively). This variant was found in the large control database ExAC at a frequency of 0.0000248 (3/121158 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as one of uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000469446 SCV000546663 uncertain significance Ataxia-telangiectasia syndrome 2018-10-30 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.

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