ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1351C>T (p.Arg451Cys) (rs201719927)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164863 SCV000215547 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164863 SCV000681971 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing
Counsyl RCV000200270 SCV000788904 uncertain significance Ataxia-telangiectasia syndrome 2016-12-21 criteria provided, single submitter clinical testing
GeneDx RCV000235327 SCV000293032 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.1351C>T at the cDNA level, p.Arg451Cys (R451C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported in at least two individuals with breast cancer (Lu 2015, Mannan 2016). ATM Arg451Cys was observed at an allele frequency of 0.07% (23/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). ATM Arg451Cys is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg451Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200270 SCV000254059 uncertain significance Ataxia-telangiectasia syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 451 of the ATM protein (p.Arg451Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201719927, ExAC 0.06%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 26689913, 26911350). ClinVar contains an entry for this variant (Variation ID: 185437). 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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