ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5250G>T (p.Trp1750Cys)

gnomAD frequency: 0.00001  dbSNP: rs587779845
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115209 SCV000149118 uncertain significance not provided 2013-11-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.5250G>T at the cDNA level, p.Trp1750Cys (W1750C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Trp1750Cys 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. This variant is a non-conservative substitution of a non-polar amino acid for a polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Trp1750Cys is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000218694 SCV000275082 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-31 criteria provided, single submitter clinical testing The p.W1750C variant (also known as c.5250G>T), located in coding exon 34 of the ATM gene, results from a G to T substitution at nucleotide position 5250. The tryptophan at codon 1750 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.
Color Diagnostics, LLC DBA Color Health RCV000218694 SCV000682257 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000627853 SCV000748737 uncertain significance Ataxia-telangiectasia syndrome 2023-10-29 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1750 of the ATM protein (p.Trp1750Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127404). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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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