ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5076A>C (p.Lys1692Asn) (rs767841041)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235459 SCV000293954 uncertain significance not provided 2016-02-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.5076A>C at the cDNA level, p.Lys1692Asn (K1692N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys1692Asn 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 Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Lys1692Asn occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Lys1692Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000470161 SCV000546924 uncertain significance Ataxia-telangiectasia syndrome 2017-02-15 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1692 of the ATM protein (p.Lys1692Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs767841041, ExAC 0.001%) but has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 246410). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000575591 SCV000667862 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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