ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7375C>T (p.Arg2459Cys) (rs730881383)

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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 RCV000165342 SCV000216066 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512906 SCV000608618 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing
Color RCV000165342 SCV000682410 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764943 SCV000896115 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000512906 SCV000293600 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.7375C>T at the cDNA level, p.Arg2459Cys (R2459C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). ATM Arg2459Cys has been reported in individuals with breast cancer or chronic lymphocytic leukemia; however, in the latter case, it is not known if this variant is germline or somatic (Cejkova 2008, Navrkalova 2013, Hauke 2018). This variant has also been observed in cancer-free controls (Tiao 2017). ATM Arg2459Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within 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 Arg2459Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000197298 SCV000254143 uncertain significance Ataxia-telangiectasia syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2459 of the ATM protein (p.Arg2459Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs730881383, ExAC 0.003%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 185845). 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 disruptive, but 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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