ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4856G>A (p.Arg1619Lys) (rs730881393)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159767 SCV000209787 uncertain significance not provided 2016-05-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.4856G>A at the cDNA level, p.Arg1619Lys (R1619K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg1619Lys 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 Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. ATM Arg1619Lys occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is not located in a known functional domain (Stracker 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Arg1619Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000213785 SCV000276801 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000539303 SCV000622536 uncertain significance Ataxia-telangiectasia syndrome 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1619 of the ATM protein (p.Arg1619Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs730881393, ExAC 0.004%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181998). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color RCV000213785 SCV000903110 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing

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