ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4329C>A (p.His1443Gln) (rs377065665)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164709 SCV000215377 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000307354 SCV000367053 uncertain significance Ataxia-telangiectasia syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000307354 SCV000546709 uncertain significance Ataxia-telangiectasia syndrome 2020-01-09 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 1443 of the ATM protein (p.His1443Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs377065665, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 185311). 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 tolerated, 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.
GeneDx RCV000521912 SCV000616645 uncertain significance not provided 2017-10-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.4329C>A at the cDNA level, p.His1443Gln (H1443Q) at the protein level,and results in the change of a Histidine to a Glutamine (CAC>CAA). This variant has not, to our knowledge, beenpublished in the literature as pathogenic or benign. ATM His1443Gln was not observed at a significant frequency inlarge population cohorts (Lek 2016). Since Histidine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM His1443Gln occurs at a position that is conserved across species and is notlocated in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have onprotein structure and function. Based on currently available evidence, it is unclear whether ATM His1443Gln is apathogenic or benign variant. We consider it to be a variant of uncertain significance
Color RCV000164709 SCV000687541 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing

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