ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7328G>A (p.Arg2443Gln) (rs587782310)

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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 RCV000131203 SCV000186153 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000131203 SCV000682405 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-16 criteria provided, single submitter clinical testing
GeneDx RCV000236663 SCV000292481 likely pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.7328G>A at the cDNA level, p.Arg2443Gln (R2443Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been identified in at least one breast cancer patient (Hauke 2018), and has been observed internally in the compound heterozygous state in two individuals with features consistent with atypical ataxia-telangiectasia. Additionally, it has been reported as a somatic variant in lymphoma, breast, colorectal, and other tumor specimens (Greiner 2006, Yip 2012, Balko 2014, Giannakis 2014). ATM Arg2443Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Arg2443Gln is located in the FAT domain (Stracker 2013). In silico analyses including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence and internal data, we consider ATM Arg2443Gln to be a likely pathogenic variant.
Invitae RCV000230833 SCV000283048 uncertain significance Ataxia-telangiectasia syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2443 of the ATM protein (p.Arg2443Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587782310, ExAC 0.006%). This variant has been observed in an individual affected with multiple cancers, including colon, prostate, multiple myeloma, melanoma and brain (Invitae). However, in that individual, a pathogenic allele was also identified in ATM, which suggests that this c.7328G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 142211). 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: "Deleterious"; PolyPhen-2: "Probably 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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