ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5228C>T (p.Thr1743Ile) (rs587779844)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115208 SCV000149117 likely pathogenic not provided 2021-04-21 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9463314, 19781682, 21933854, 27978560, 32832836, 31921190, 33436325, 30303537, 22529920, 19431188, 26582918, 21792198, 19147735, 30549301, 17968022, 21787400, 20346647)
Invitae RCV000168297 SCV000218976 pathogenic Ataxia-telangiectasia syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1743 of the ATM protein (p.Thr1743Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs587779844, ExAC 0.003%). This variant has been observed in individuals affected with ataxia-telangiectasia (A-T) (PMID: 9463314, 21792198, 19147735, 31921190), chronic lymphocytic leukemia (PMID: 21933854, 17968022), breast cancer (PMID: 19781682, 30303537), and colon cancer (PMID: 27978560). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127403). This variant has been reported to affect ATM protein function (PMID: 19431188). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000220146 SCV000272973 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-25 criteria provided, single submitter clinical testing The p.T1743I variant (also known as c.5228C>T), located in coding exon 34 of the ATM gene, results from a C to T substitution at nucleotide position 5228. The threonine at codon 1743 is replaced by isoleucine, an amino acid with similar properties. <span style="background-color:initial">Multiple individuals with ataxia telangiectasia have been found to carry this alteration in combination with a truncating ATM mutation; however, phase of the alterations was not determined (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Mandola AB et al. Front Immunol, 2019 Dec;10:2940<span style="background-color:initial">). Subsequently, cells from one of these patients were shown to express low levels of mutant protein but did not display any ATM kinase activity based on immunoblotting following irradiation (<span style="background-color:initial">Reiman A et al. Br. J. Cancer. 2011 Aug;105:586-91<span style="background-color:initial">). Another study evaluating kinase activity found that this alteration resulted in reduced, but not eliminated, phosphorylation of downstream targets compared to positive controls (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). This alteration has been detected in multiple breast cancer patients but not in matched healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Caminsky NG et al. Hum. Mutat., 2016 07;37:640-52; Girard E et al. Int. J. Cancer. 2019 04;144:1962-1974).<span style="background-color:initial"> This alteration was identified in the germline of one patient with chronic lymphocytic leukemia in conjunction with loss of heterozygosity at chromosome 11q (Skowronska A et al. Haematologica. 2012 Jan;97:142-6). Computational analyses using in silico tools classify this variant as having unknown or borderline potential for pathogenicity (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; George Priya Doss C et al. PLoS One. 2012 Apr;7:e34573). <span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Counsyl RCV000168297 SCV000800744 uncertain significance Ataxia-telangiectasia syndrome 2018-04-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000220146 SCV000904618 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000115208 SCV001143113 pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism.
Mayo Clinic Laboratories, Mayo Clinic RCV000115208 SCV001713579 pathogenic not provided 2020-05-14 criteria provided, single submitter clinical testing PM3_Strong, PS3_moderate, PS4_moderate, PP3, PP4

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