ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7211A>G (p.Tyr2404Cys)

dbSNP: rs1064794093
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482617 SCV000567798 uncertain significance not provided 2015-08-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.7211A>G at the cDNA level, p.Tyr2404Cys (Y2404C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr2404Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr2404Cys occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Tyr2404Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000798283 SCV000937890 uncertain significance Ataxia-telangiectasia syndrome 2022-01-12 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 419765). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2404 of the ATM protein (p.Tyr2404Cys).
Ambry Genetics RCV002374892 SCV002668742 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-24 criteria provided, single submitter clinical testing The p.Y2404C variant (also known as c.7211A>G), located in coding exon 48 of the ATM gene, results from an A to G substitution at nucleotide position 7211. The tyrosine at codon 2404 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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