Submissions for variant NM_000051.4(ATM):c.670A>G (p.Lys224Glu)

gnomAD frequency: 0.00009  dbSNP: rs145053092

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131698	SCV000186735	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-27	criteria provided, single submitter	clinical testing	The p.K224E variant (also known as c.670A>G), located in coding exon 6 of the ATM gene, results from an A to G substitution at nucleotide position 670. The lysine at codon 224 is replaced by glutamic acid, an amino acid with similar properties. This variant was reported in an individual with ataxia telangiectasia who also carried an ATM pathogenic mutation, however, detailed clinical information and the phase of the two detected alterations were not provided (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7). This alteration has been detected in 1/4112 breast cancer patients and 1/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration has also been identified in breast, pancreatic, prostate and melanoma cohorts, as well as in a pediatric leukemia case (Zhang J et al. N. Engl. J. Med. 2015 Dec;373(24):2336-2346; Decker B et al. J. Med. Genet. 2017 11;54(11):732-741; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Bradbury et al. JCO Precis. Oncol. 2018 Apr;2; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Li C et al. Melanoma Res. 2020 Jun;30(3):247-251; Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000587384	SCV000209679	uncertain significance	not provided	2024-11-08	criteria provided, single submitter	clinical testing	Observed in the compound heterozygous state with an ATM truncating variant in a patient with ataxia-telangiectasia (PMID: 10817650); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 24825865, 19781682, 23585524, 22114986, 28779002, 29659569, 29522266, 29449575, 26580448, 27616075, 29684080, 25186627, 20305132, 31422574, 31920950, 31567591, 33436325, 32095738, 33471991, 30303537, 34326862, 34262154, 36029002, 33850299, 35534704, 10817650, 38136308)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205199	SCV000259665	likely benign	Ataxia-telangiectasia syndrome	2025-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211951	SCV000593495	uncertain significance	not specified	2016-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131698	SCV000682362	likely benign	Hereditary cancer-predisposing syndrome	2020-08-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211951	SCV000694330	uncertain significance	not specified	2023-03-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.670A>G (p.Lys224Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-05 in 258294 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.9e-05 vs 0.004), allowing no conclusion about variant significance. c.670A>G has been reported in the literature in an individual affected with Ataxia-Telangiectasia (Li_2000) and in several individuals affected with various types of cancers (example, Tavtigian_2009, Kraus_2016, Paulo_2018, Dalmasso_2021, Karlsson_2021). The variant has also been observed in unaffected control individuals (example, Tavtigian_2009, Girard_2019). These data do not allow any conclusion about variant significance. At-least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Navrkalova_2013). 12 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and three ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Eurofins Ntd Llc (ga)	RCV000587384	SCV000703935	uncertain significance	not provided	2017-01-04	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000205199	SCV000803585	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Ataxia telangiectasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.
CeGaT Center for Human Genetics Tuebingen	RCV000587384	SCV001148400	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	ATM: BP4
Division of Medical Genetics, University of Washington	RCV001257492	SCV001434303	uncertain significance	Familial cancer of breast	2020-04-24	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in individuals with breast cancer (Tavtigian 2009, Bernstein 2010, Lu 2015, Kraus 2017) and in an individual with ataxia-telangiectasia who had a frameshift variant in the ATM gene on the other allele (Li 2000). This variant has an overall allele frequency of 0.00009 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3; PM3
Baylor Genetics	RCV000205199	SCV001481322	uncertain significance	Ataxia-telangiectasia syndrome	2019-07-31	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000587384	SCV001714392	uncertain significance	not provided	2020-07-31	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587384	SCV002010791	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131698	SCV002538415	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211951	SCV004027141	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001257492	SCV004208121	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587384	SCV004222052	uncertain significance	not provided	2024-10-11	criteria provided, single submitter	clinical testing	The ATM c.670A>G (p.Lys224Glu) variant has been reported in the published literature in an individual affected with ataxia-telangiectasia along with another pathogenic ATM variant (PMID: 10817650 (2000)) and in individuals with breast cancer (PMID: 19781682 (2009), 20305132 (2010), 26689913 (2015), 27616075 (2016), 28779002 (2017)), melanoma (PMID: 34262154 (2021)), and prostate cancer (PMID: 33436325 (2021)). This variant has also been observed in reportedly healthy individuals (PMID: 19781682 (2009), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.0002 (10/50682 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Athena Diagnostics	RCV000587384	SCV004229305	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The available data on the frequency of this variant in large general population databases was not informative towards the evaluation of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features of ataxia-telangiectasia. Computational tools disagree on the variant's effect on normal protein function.
Myriad Genetics, Inc.	RCV001257492	SCV006093161	likely benign	Familial cancer of breast	2025-03-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV004551265	SCV000805607	uncertain significance	ATM-related disorder	2024-01-22	no assertion criteria provided	clinical testing	The ATM c.670A>G variant is predicted to result in the amino acid substitution p.Lys224Glu. This variant was reported in the compound heterozygous state with another variant in a patient with ataxia telangiectasia (Li et al. 2000. PubMed ID: 10817650). It was also reported in a patient with triple negative breast cancer and a family history of cervical and pancreatic cancer (Kraus et al. 2016. PubMed ID: 27616075, Suppl. Table 4). This variant has also been reported in additional individuals with breast cancer (Bernstein et al. 2010. PubMed ID: 20305132, Suppl. Table 2; Lu et al. 2015. PubMed ID: 26689913, Suppl. Table 12). However, in another study, it was reported at similar frequencies in cases and controls (Tavtigian et al. 2009. PubMed ID: 19781682, Suppl. Table 2). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142522/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000205199	SCV001454842	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587384	SCV001740622	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587384	SCV001906420	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587384	SCV001930593	uncertain significance	not provided		no assertion criteria provided	clinical testing