ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7381C>T (p.Arg2461Cys) (rs201314561)

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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 RCV000131731 SCV000186771 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000212067 SCV000209643 uncertain significance not provided 2018-12-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.7381C>T at the cDNA level, p.Arg2461Cys (R2461C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been reported in individuals with endometrial, sarcoma, prostate, and colorectal tumors (Ballinger 2016, Pearlman 2016, Ring 2016, Beebe-Dimmer 2018). ATM Arg2461Cys was observed at an allele frequency of 0.06% (15/24,036) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg2461Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206694 SCV000259652 uncertain significance Ataxia-telangiectasia syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2461 of the ATM protein (p.Arg2461Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201314561, ExAC 0.07%). This variant has been observed in individuals affected with sarcoma, endometrial, colorectal and prostate cancer (PMID: 27498913, 27443514, 27978560, 29356034). ClinVar contains an entry for this variant (Variation ID: 142541). 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 C15"). 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.
Color RCV000131731 SCV000537581 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing
Counsyl RCV000206694 SCV000800335 uncertain significance Ataxia-telangiectasia syndrome 2018-06-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764944 SCV000896116 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing

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