ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1601C>G (p.Pro534Arg) (rs587782212)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130890 SCV000185798 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-13 criteria provided, single submitter clinical testing The p.P534R variant (also known as c.1601C>G) located in coding exon 9 of the ATM gene. This variant results from a C to G substitution at nucleotide position 1601. The proline at codon 534 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 66000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.P534R remains unclear.
Invitae RCV001070274 SCV001235496 uncertain significance Ataxia-telangiectasia syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 534 of the ATM protein (p.Pro534Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 142071). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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