ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1748A>G (p.Tyr583Cys) (rs587780614)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218850 SCV000276436 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000218850 SCV000911232 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590682 SCV000859953 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing
GeneDx RCV000590682 SCV000209777 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.1748A>G at the cDNA level, p.Tyr583Cys (Y583C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was observed in at least five individuals with breast cancer (Decker 2017, Hauke 2018). ATM Tyr583Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Tyr583Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000228653 SCV000367031 uncertain significance Ataxia-telangiectasia syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590682 SCV000694197 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing Variant summary: The ATM c.1748A>G (p.Tyr583Cys) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). Tyr583 is not located in any known functional domain and is not highly conserved across species. This variant was found in 1/121140 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant was reported to have been identified in one sample from a large panel of HNSCC-derived cells (Martin_Oncotarget_2014), but has not been cited in patients in the literature. In addition, multiple clinical diagnostic laboratories classified this variant as a VUS. In the absence of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000228653 SCV000282881 uncertain significance Ataxia-telangiectasia syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 583 of the ATM protein (p.Tyr583Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs587780614, ExAC 0.006%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181989). 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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