Submissions for variant NM_000051.4(ATM):c.6154G>A (p.Glu2052Lys)

gnomAD frequency: 0.00001  dbSNP: rs202206540

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212039	SCV000209758	likely pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing	Observed in individuals with breast and other cancers (Kraus et al., 2017; Lilyquist et al., 2017; Hampel et al., 2018; Singh et al., 2018; Adaniel et al., 2019; Lu et al., 2019; Toss et al., 2021; Ayaz et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30548122, 29470806, 28888541, 23532176, 25572163, 24220272, 27616075, 10330348, 31125277, 30128536, 29596542, 31407689, 30363071, 32860008, 31216378, 32832836, 34426522, 33919281, 33098801, Blanchard-Rohner[article], 35154108, 29922827, Ayaz2022[article], 34954471, 23946315)
Ambry Genetics	RCV000159743	SCV000216022	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-30	criteria provided, single submitter	clinical testing	The p.E2052K variant (also known as c.6154G>A), located in coding exon 41 of the ATM gene, results from a G to A substitution at nucleotide position 6154. The glutamic acid at codon 2052 is replaced by lysine, an amino acid with similar properties. This variant has been reported in a homozygous state in an individual with ataxia telangiectasia (A-T) (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31). Further, Teraoka et al. state this individual only produced transcripts with the deletion of exon 44 (coding exon 41), leading to a frameshift, and western blotting of lysates failed to reveal any ATM protein. This variant has also been reported in a compound heterozygous state in multiple individuals with dystonia, but without ataxia and telangiectasia (Necpál J et al. Mov Disord Clin Pract. Dec;5:89-91; Rudenskaya GE et al. Zh Nevrol Psikhiatr Im S S Korsakova, 2019;119:101-106; Blanchard-Rohner G et al. Front Immunol, 2022 Jan;13:791522), and in 3 siblings with dopa-responsive dystonia (Charlesworth G et al. Neurology. 2013 Sep; 81(13):1148-51). The p.E2052K variant has also been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170:189-196; Fu F et al. Cancer Biol Med, 2021 Oct;19:253-62; Toss A et al. Genes (Basel), 2021 Apr;12:). This alteration has been identified in a Chilean woman diagnosed with triple-negative breast cancer at age 50 and papillary serous ovarian cancer at age 61, as well as her daughter who was diagnosed with thyroid cancer at age 31; however, they both also had the RAD51C c.404G>A likely pathogenic variant (Adaniel C et al. J Glob Oncol. 2019 May;5:1-14). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classical ataxia-telangiectasia; however, it may be associated with dystonia and may lead to increased risk of developing ATM-related cancer. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000167963	SCV000218611	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2052 of the ATM protein (p.Glu2052Lys). This variant is present in population databases (rs202206540, gnomAD 0.04%). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or with features of non-classical A-T, several of whom present with dystonia without ataxia and telangiectasia. This variant might be associated with non-classical A-T. It has also been observed in individuals with ovarian cancer and breast cancer (PMID: 10330348, 27616075, 28888541, 29470806, 30363071, 31216378, 31407689, 35154108). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in ATM in an individual who was not affected with recessive ATM-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 181975). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000159743	SCV000911078	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-12	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2052 in the FAT domain of the ATM protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant was first reported in the literature in the homozygous state in an individual affected with autosomal recessive ataxia-telangiectasia (PMID: 10330348). In a cell line derived from this patient, an abnormal transcript containing out-of-frame skipping of exon 42 was detected (referred to as exon 44 in this article based on the exon/intron definition described in PMID: 8660985), and there was no ATM protein expression detectable by Western blot. This p.Glu2052Lys (c.6154G>A) variant was the only variant detected upon sequencing of exons 41-44 (referred to as exons 43-46 in the article) and flanking intronic sequences. The remaining regions of the ATM gene were not sequenced, and whether this variant was the cause of observed skipping of exon 42 was not investigated in this study. This variant has been observed in the compound heterozygous state with other pathogenic ATM variants in individuals affected with ataxia-telangiectasia and dystonia (PMID: 23946315, 30363071, 31407689, 35154108). Lymphoblastoid cell lines derived from two of these individuals, a brother and sister affected with variant ataxia-telangiectasia, showed reduced levels of ATM expression and ATM activity (PMID: 35154108). However, this variant has also been detected in the compound heterozygous state with a pathogenic variant in the ATM gene in an individual who was unaffected with ataxia-telangiectasia (ClinVar: SCV000218611.10), suggesting that this variant may not contribute to disease. This variant has been reported in heterozygous individuals affected with breast cancer and/or ovarian cancer (PMID: 27616075, 29470806, 30128536, 32125938, 32860008, 33919281; DOI: 10.14744/ejmo.2022.88057), prostate cancer (PMID: 32832836), and colorectal cancer (PMID: 29470806). It has also been observed in an individual affected with breast and ovarian cancer and in her daughter affected with thyroid cancer, both of whom were carriers of a pathogenic RAD51C germline variant (PMID: 31125277). This variant occurs at an elevated allele frequency in the general population: it has been observed in 16/282788 total chromosomes by the Genome Aggregation Database (15 alleles in the non-cancer cohort) and in 12/30612 South Asian chromosomes (0.0392%; all 12 alleles in the non-cancer cohort). In summary, the reported clinical findings in individuals who carry this variant are contradictory, and the mechanism by which this variant may cause disease is not known. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000167963	SCV001150023	likely pathogenic	Ataxia-telangiectasia syndrome	2019-06-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000167963	SCV001163272	likely pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001251135	SCV001426633	pathogenic	Familial cancer of breast		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000212039	SCV001475562	uncertain significance	not provided	2019-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167963	SCV001482190	likely pathogenic	Ataxia-telangiectasia syndrome	2021-02-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6154G>A (p.Glu2052Lys) results in a conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Though 4/4 computational tools predicted no significant impact on normal splicing, one publication reported that in a patient derived lymphoblastoid cell line (LCL), which had the variant in homozygous state, only ATM transcripts with exon 42 skipping (exon 44 in the report) could be detected (Teraoka_1999). However, authors also noted that several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation of their data. This exon deletion is predicted to result in a frameshift at the protein level, and authors of the study noted that they couldn't demonstrate any ATM protein on a Western blot from the lysates of this cell line (data were not shown; Teraoka_1999). The variant allele was found at a frequency of 5.7e-05 in 282788 control chromosomes, predominantly at a frequency of 0.0004 within the South Asian subpopulation in the gnomAD database. However, the variant was reported with an even higher frequency (0.001) in Indian subpopulations (i.e. found in 6/2793 healthy heterozygous individuals; see Narang_2020 and LOVD). These frequencies are somewhat lower than the maximum expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.004), allowing no clear conclusions about variant significance. This variant, c.6154G>A, has been observed with a second pathogenic ATM variant in trans in several individuals who had a milder phenotype of ataxia telangiectasia (e.g. Charlesworth_2013, Necpal_2018, Rudenskaya_2019, Carecchio_2019); these patients typically had segmental dystonia in some cases with conjunctival telangiectasia, a phenotype corresponding to variant ataxia telangiectasia, characteristic to missense mutations that leave some residual ATM kinase activity (see e.g. PMID 30549301). The variant was also reported in several individuals with a personal and/or family history of breast and/or ovarian cancer or other tumor phenotypes (e.g. Kraus_2016, Singh_2018, Lu_2019, Adaniel_2019, Yadav_2020, Matejcic_2020), however in one of these reports a co-occurrence with a likely pathogenic variant (RAD51C c.404G>A, p.Cys135Tyr) has been described in an affected woman (breast and ovarian cancer) as well as in her daughter (thyroid cancer), providing supporting evidence for a benign role (Adaniel_2019). Seven submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant with conflicting assessments, i.e. as pathogenic (n=1) / likely pathogenic (n=3) or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic for a milder phenotype of ataxia telangiectasia.
Genetic Services Laboratory, University of Chicago	RCV000212039	SCV002067476	likely pathogenic	not provided	2020-04-28	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.6154G>A, in exon 42 that results in an amino acid change, p.Glu2052Lys. This sequence change has been described in few individuals with breast cancer but no additional evidence was provided in these studies to assess its pathogenicity (PMIDs: 27616075, 29470806, 31125277). It has also been described in a compound heterozygous state with a different pathogenic truncating variant in two families with Dopa-responsive dystonia and isolated craniocervical dystonia respectively (PMIDs: 23946315, 30363071). Teraoka et al., 1999 described this change in the homozygous state in an individual with ataxia-telangiectasia (AT). Functional studies performed by this group revealed absence of ATM protein by Western blotting and ATM transcripts with missing exon 44 (PMID: 10330348). They postulated that the variant may cause defective splicing by disrupting the formation of the spliceosome as this variant does not affect any known splicing-control motif. This sequence change has been described in the gnomAD database with a low population frequency of 0.039% in the South Asian subpopulation (dbSNP rs202206540). The p.Glu2052Lys change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu2052Lys substitution. This sequence change is likely to be pathogenic in relation to an autosomal recessive Ataxia-telangiectasia variant phenotype; however, its possible contribution to an autosomal dominant hereditary cancer predisposition phenotype is unclear.
Sema4, Sema4	RCV000159743	SCV002537133	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-03	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV001251135	SCV003925623	uncertain significance	Familial cancer of breast	2023-04-03	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4_MOD, PP3
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001251135	SCV003936017	likely pathogenic	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing	A likely pathogenic mutationsin the ATM gene (c.6154G>A). This sequence change results in a moderately conserved amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. In-silico predictions show Pathogenic computational verdict based on 8 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor and MutationTaster vs 4 benign predictions from BayesDel_addAF, DEOGEN2, PrimateAI and SIFT. The variant allele was found at a frequency of 5.7e-05 in 282788 control chromosomes, predominantly at a frequency of 0.0004 within the South Asian subpopulation in the gnomAD database. However, the variant was reported with an even higher frequency (0.001) in Indian subpopulations (Narang 2020). This variant, c.6154G>A, has been observed with a second pathogenic ATM variant in trans in several individuals who had a milder phenotype of ataxia telangiectasia (e.g. Charlesworth_2013, Necpal_2018, Rudenskaya_2019, Carecchio_2019); these patients typically had segmental dystonia in some cases with conjunctival telangiectasia, a phenotype corresponding to variant ataxia telangiectasia, characteristic to missense mutations that leave some residual ATM kinase activity (see e.g. PMID 30549301). The variant was also reported in several individuals with a personal and/or family history of breast and/or ovarian cancer or other tumor phenotypes (e.g. Kraus_2016, Singh_2018, Lu_2019, Adaniel_2019, Yadav_2020, Matejcic_2020), however in one of these reports a co-occurrence with a likely pathogenic variant (RAD51C c.404G>A, p.Cys135Tyr) has been described in an affected woman (breast and ovarian cancer) as well as in her daughter (thyroid cancer), providing supporting evidence for a benign role (Adaniel_2019). Therefore, this variant has been classified as likely pathogenic.
Baylor Genetics	RCV001251135	SCV004203838	likely pathogenic	Familial cancer of breast	2024-02-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212039	SCV004221222	uncertain significance	not provided	2019-10-28	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 27616075 (2016), 29470806 (2018), 30128536 (2018), 32125938 (2020), 32860008 (2020), 33919281 (2021), 34606182 (2021), 35734982 (2022)), prostate cancer (PMID: 32832836 (2020)), and healthy individuals (PMID: 36243179 (2023), and FLOSSIES (https://whi.color.com)). Additionally, this variant has been seen in individuals with ataxia telangiectasia (AT) both homozygously (PMID: 10330348 (1999)) and compound heterozygously with additional pathogenic variants in the ATM gene (PMIDs: 31407689 (2019), 35154108 (2022)). Experimental studies are inconclusive on the variant's impact on proper protein function (PMID: 10330348 (1999), 35154108 (2022)). The frequency of this variant in the general population, 0.00039 (12/30612 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneReviews	RCV000167963	SCV000328267	not provided	Ataxia-telangiectasia syndrome		no assertion provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357434	SCV001552904	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Glu2052Lys variant was identified in 7 of 1268 proband chromosomes (frequency: 0.006) from individuals with Ataxia Telangiectasia, Cervical Dopa-Responsive Dystonia, and breast or ovarian cancer (Teraoka 1999, Kraus 2017, Charlesworth 2013, Necpal 2017). The variant was identified in dbSNP (rs202206540) as “with likely pathogenic allele”, ClinVar (classified as likely pathogenic by Ambry Genetics and GeneDx; as uncertain significance by Invitae and Color; and as pathogenic by GeneReviews) and LOVD 3.0 (observed 2x). The variant was identified in control databases in 16 of 277,144 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,026 chromosomes (freq: 0.00004), European in 3 of 126,668 chromosomes (freq: 0.00002), and South Asian in 12 of 30,778 chromosomes (freq: 0.0004); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian or Finnish populations. A Western blot run on a lymphoblastoid cell line derived from a patient with Ataxia-Telangiectasia who was homozygous for this variant showed an absence of ATM protein (Teraoka 1999). Three patients from one family who all presented with Cervical Dopa-Responsive Dystonia were compound heterozygotes for this variant and a pathogenic ATM variant (p.Ile2629Serfs), which segregated in trans (Charlesworth 2013) and another patient that presented with “variant” Ataxia Telangiectasia, a milder form of the disease, was identified as a compound heterozygote with a pathogenic ATM variant (p.Trp1858*) that was shown to occur in trans (Necpal 2017). However, this variant has been identified by an external laboratory as co-occurring in trans with a pathogenic ATM variant in a patient who was not affected with ataxia telangiectasia (Invitae internal data per ClinVar submission dated March 29, 2019). The p.Glu2052 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212039	SCV001980156	uncertain significance	not provided		no assertion criteria provided	clinical testing