ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2945G>A (p.Arg982His) (rs749471737)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164299 SCV000214929 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000164299 SCV000682092 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Counsyl RCV000476746 SCV000799718 uncertain significance Ataxia-telangiectasia syndrome 2018-05-02 criteria provided, single submitter clinical testing
GeneDx RCV000235707 SCV000293004 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.2945G>A at the cDNA level, p.Arg982His (R982H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in an individual with colorectal cancer undergoing multigene hereditary cancer panel testing (Yurgelun 2017). ATM Arg982His was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Arg982His is within 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 Arg982His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000164299 SCV000821844 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000476746 SCV000546810 uncertain significance Ataxia-telangiectasia syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 982 of the ATM protein (p.Arg982His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs749471737, ExAC 0.01%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 184953). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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