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
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.
Ambry Genetics RCV000218850 SCV000276436 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence
Invitae RCV000228653 SCV000282881 likely benign Ataxia-telangiectasia syndrome 2019-12-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000228653 SCV000367031 uncertain significance Ataxia-telangiectasia syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590682 SCV000859953 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing
Color RCV000218850 SCV000911232 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-05 criteria provided, single submitter clinical testing

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