ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5228C>T (p.Thr1743Ile)

gnomAD frequency: 0.00001  dbSNP: rs587779844
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115208 SCV000149117 pathogenic not provided 2023-12-22 criteria provided, single submitter clinical testing Observed in the heterozygous state in individuals with a personal or family history including breast, pancreatic, and other cancers (PMID: 19781682, 30303537, 27978560, 21933854, 35047863); 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: 21792198, 21787400, 17968022, 26582918, 19431188, 20346647, 21933854, 22529920, 27978560, 30549301, 19147735, 30303537, 9463314, 19781682, 32832836, 34771661, 33436325, 32853339, 35078243, 34539671, 26896183, 31921190, 35047863, 29922827, 33471991, 36623239, 34326862, 26898890, 37712079, 28779002, 16014569)
Labcorp Genetics (formerly Invitae), Labcorp RCV000168297 SCV000218976 pathogenic Ataxia-telangiectasia syndrome 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1743 of the ATM protein (p.Thr1743Ile). This variant is present in population databases (rs587779844, gnomAD 0.004%). This missense change has been observed in individual(s) with ataxia-telangiectasia (A-T) (PMID: 9463314, 17968022, 19147735, 19781682, 21792198, 21933854, 27978560, 30303537, 31921190). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127403). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 19431188). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000220146 SCV000272973 pathogenic Hereditary cancer-predisposing syndrome 2022-08-05 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. 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; Nahas SA et al. Clin Chem, 2009 Mar;55:463-72; Mandola AB et al. Front Immunol, 2019 Dec;10:2940; Jackson TJ et al. Dev Med Child Neurol 2016 07;58(7):690-7). 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 (Reiman A et al. Br. J. Cancer. 2011 Aug;105:586-91). 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 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; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant was reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV000220146 SCV000904618 pathogenic Hereditary cancer-predisposing syndrome 2023-01-30 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 1743 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant protein had reduced kinase activity in a cell-based assay (PMID: 19431188). This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 9463314, 21792198, 31921190). This variant has also been reported in individuals affected with breast cancer (PMID: 19781682, 28779002, 30303537, 33471991), prostate cancer (PMID: 33436325), and colon cancer (PMID: 27978560) and has been reported to segregate with breast cancer in one family (Tischkowitz et al. ESMO Preceptorship on Hereditary Cancer Genetics 2019). This variant has been identified in 5/282558 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Athena Diagnostics 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
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town RCV000168297 SCV003930348 likely pathogenic Ataxia-telangiectasia syndrome 2024-05-22 criteria provided, single submitter research PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00008476 (0.008%; 100/1179784 alleles in European non Finnish population). PM3_strong: 3 points awarded for 3 observations of variant with pathogenic variants confirmed in trans (PMID: 31921190, 19147735, 9463314). PP3_moderate: REVEL score is 0.83. PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product. PS4 not evaluated as affected literature probands with variant already counted under PM3. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Baylor Genetics RCV003460805 SCV004208845 pathogenic Familial cancer of breast 2024-03-18 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003460805 SCV004932208 likely pathogenic Familial cancer of breast 2024-01-25 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31921190,19147735, 26896183, 9463314, 37438524]. Functional studies indicate this variant impacts protein function [PMID: 19431188, 26896183, 9463314].
Counsyl RCV000168297 SCV000800744 uncertain significance Ataxia-telangiectasia syndrome 2018-04-12 flagged submission clinical testing

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