ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2222A>G (p.Tyr741Cys) (rs878853492)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226596 SCV000282892 uncertain significance Ataxia-telangiectasia syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 741 of the ATM protein (p.Tyr741Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 236685). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000589621 SCV000567220 uncertain significance not provided 2018-10-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.2222A>G at the cDNA level, p.Tyr741Cys (Y741C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was observed in at least one individual with breast cancer (Decker 2017). ATM Tyr741Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a cryptic splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether ATM Tyr741Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572488 SCV000660654 likely benign Hereditary cancer-predisposing syndrome 2017-10-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000589621 SCV000694211 uncertain significance not provided 2016-05-20 criteria provided, single submitter clinical testing Variant summary: The ATM c.2222A>G (p.Tyr741Cys) 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). This variant was absent in 121224 control chromosomes, and has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV000572488 SCV000911160 likely benign Hereditary cancer-predisposing syndrome 2016-02-29 criteria provided, single submitter clinical testing

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