ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6056A>G (p.Tyr2019Cys) (rs876658415)

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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 RCV000216689 SCV000273593 likely pathogenic Hereditary cancer-predisposing syndrome 2015-01-16 criteria provided, single submitter clinical testing The p.Y2019C variant (also known as c.6056A>G), located in coding exon 40 of the ATM gene, results from an A to G substitution at nucleotide position 6056. The tyrosine at codon 2019 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in a compound heterozygous state along with the p.L2338P (c.7013T) alteration in a 7 year old girl with Ataxia-Telangiectasia. Functional impact of these alterations was assessed via western blot and indicated 0% ATM protein expression (Carney EF et al, J. Immunol. 2012 Jul; 189(1):261-8). Another study assessed the stability and kinase activity of multiple ATM variants and found that this variant resulted in ATM expression but with no detectable downstream kinase activity (Barone G et al, Hum. Mutat. 2009 Aug; 30(8):1222-30).<span style="font-size:13.3333339691162px"> This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000543617 SCV000622634 uncertain significance Ataxia-telangiectasia syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2019 of the ATM protein (p.Tyr2019Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in one individual affected with ataxia-telangiectasia (PMID: 19431188, 22649200). ClinVar contains an entry for this variant (Variation ID: 230152). Experimental studies have shown that this missense change abolishes ATM kinase activity (PMID: 19431188). In summary, this variant is a rare missense change with that has been reported to impact protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to conclusively determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000216689 SCV000911956 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001251347 SCV001426913 uncertain significance not specified 2020-07-16 criteria provided, single submitter clinical testing Variant summary: ATM c.6056A>G (p.Tyr2019Cys) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes (gnomAD). c.6056A>G has been reported in the literature in at least one individual affected with Ataxia-Telangiectasia (Carney_2012). These data however, do not allow any conclusion about variant significance. In a functional study, the variant showed absence of ATM kinase activity on its downstream targets (Barone_2009). Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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