ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2408T>C (p.Phe803Ser) (rs751218526)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000777664 SCV000913566 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000484668 SCV000571099 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.2408T>C at the cDNA level, p.Phe803Ser (F803S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTC>TCC). This variant was observed in a normal tissue sample from an individual with endometrial carcinoma (Lu 2015). ATM Phe803Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Phe803Ser occurs at a position where amino acids with properties similar to Phenylalanine are tolerated across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Phe803Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000804031 SCV000943922 uncertain significance Ataxia-telangiectasia syndrome 2018-07-15 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 803 of the ATM protein (p.Phe803Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs751218526, ExAC 0.002%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 421790). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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