ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4303A>C (p.Lys1435Gln) (rs876660964)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562594 SCV000660606 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000562594 SCV000687537 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000216209 SCV000278826 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.4303A>C at the cDNA level, p.Lys1435Gln (K1435Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys1435Gln 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 Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Lys1435Gln occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Lys1435Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000704673 SCV000833630 uncertain significance Ataxia-telangiectasia syndrome 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 1435 of the ATM protein (p.Lys1435Gln). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 234267). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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