ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1373G>A (p.Cys458Tyr)

dbSNP: rs1064796013
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000628187 SCV000749080 uncertain significance Ataxia-telangiectasia syndrome 2024-03-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 458 of the ATM protein (p.Cys458Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 32488064, 32775531, 33084218). ClinVar contains an entry for this variant (Variation ID: 524415). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Color Diagnostics, LLC DBA Color Health RCV001525983 SCV001736214 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-22 criteria provided, single submitter clinical testing This missense variant replaces cysteine with tyrosine at codon 458 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in the compound heterozygous in an individual affected with mild ataxia-telangiectasia (PMID: 32775531). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001525983 SCV002698041 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-03 criteria provided, single submitter clinical testing The p.C458Y variant (also known as c.1373G>A), located in coding exon 9 of the ATM gene, results from a G to A substitution at nucleotide position 1373. The cysteine at codon 458 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been identified with an ATM likely pathogenic variant in an individual with clinical features of ataxia-telangiectasia (Perez Maturo J et al. J Hum Genet, 2020 Oct;65:895-902; Perez Maturo J et al. Mov Disord Clin Pract, 2020 Aug;7:727-729; Salinas V et al. Am J Med Genet C Semin Med Genet, 2020 12;184:876-884). 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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