ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6482G>A (p.Arg2161His) (rs756626462)

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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 RCV000164617 SCV000215281 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Color RCV000164617 SCV000903397 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000235276 SCV000293556 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.6482G>A at the cDNA level, p.Arg2161His (R2161H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). ATM Arg2161His 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; however it was identified in one control individual in a meta-analysis of breast cancer cases and controls (Tavtigian 2009). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. ATM Arg2161His occurs at a position that is not conserved and is located in the FAT domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Arg2161His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000470832 SCV000546775 uncertain significance Ataxia-telangiectasia syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2161 of the ATM protein (p.Arg2161His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with an ATM-related disease, but has been reported in a control individual from a breast cancer study (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 185236). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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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