Submissions for variant NM_000051.4(ATM):c.6056A>G (p.Tyr2019Cys)

gnomAD frequency: 0.00001  dbSNP: rs876658415

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216689	SCV000273593	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-20	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>C) alteration in a seven-year old female 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543617	SCV000622634	uncertain significance	Ataxia-telangiectasia syndrome	2023-09-12	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2019 of the ATM protein (p.Tyr2019Cys). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 19431188, 22649200, 26896183, 30549301). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 19431188). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 230152).
Color Diagnostics, LLC DBA Color Health	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	2023-09-01	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 as a compound heterozygous genotype in at least one individual affected with Ataxia-Telangiectasia (Carney_2012). These data do not allow any conclusion about variant significance. In a functional study, the variant was expressed at normal levels and was able to autophosphorylate ATM serine 1981, but showed an absence of ATM kinase activity on its downstream targets (Barone_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 22649200). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two submitters classified the variant as uncertain significance and one submitter classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV004701282	SCV005201684	likely pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing	Published in vitro assay showed this variant to result in loss of kinase activity against multiple downstream targets (PMID: 19431188); Observed in individual(s) with breast cancer (PMID: 28779002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27479817, 28188106, 22649200, 25480502, 26466571, 11382771, 35710297, 34771661, 37507074, 23532176, 36550207, 30549301, 26896183, 19431188, 28779002)