ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3899A>G (p.Tyr1300Cys) (rs183263185)

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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 RCV000159719 SCV000216595 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000159719 SCV000687506 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-16 criteria provided, single submitter clinical testing
Counsyl RCV000398586 SCV000791970 uncertain significance Ataxia-telangiectasia syndrome 2017-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000212005 SCV000209731 uncertain significance not provided 2018-04-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.3899A>G at the cDNA level, p.Tyr1300Cys (Y1300C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr1300Cys was observed at an allele frequency of 0.04% (12/30780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr1300Cys 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 information, it is unclear whether ATM Tyr1300Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000398586 SCV000367049 uncertain significance Ataxia-telangiectasia syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000398586 SCV000546823 uncertain significance Ataxia-telangiectasia syndrome 2018-10-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1300 of the ATM protein (p.Tyr1300Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs183263185, ExAC 0.05%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181952). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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