ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6154G>A (p.Glu2052Lys) (rs202206540)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212039 SCV000209758 likely pathogenic not provided 2021-05-21 criteria provided, single submitter clinical testing Observed in individuals with breast and other cancers (Kraus 2017, Hampel 2018, Singh 2018, Adaniel 2019, Lu 2019); 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, 23532176, 25572163, 24220272, 27616075, 10330348, 31125277, 30128536, 29596542, 31407689, 30363071, 32860008, 31216378, 23946315, 32832836, 33098801)
Ambry Genetics RCV000159743 SCV000216022 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-03 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 an individual with isolated segmental dystonia, but without ataxia and telangiectasia (Necpál J et al. Mov Disord Clin Pract. Dec;5:89-91), 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). 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 the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000167963 SCV000218611 uncertain significance Ataxia-telangiectasia syndrome 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2052 of the ATM protein (p.Glu2052Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs202206540, ExAC 0.03%). This variant has been reported to segregate in one family with dopa-responsive dystonia in individuals who also carry a loss-of-function variant (c.7886_7890del) on the opposite chromosome (in trans) in the ATM gene. One family member who presented with typical manifestations of ataxia-telangiectasia (A-T) was homozygous for the c.7886_7890del variant and did not carry the p.Glu2052Lys variant (PMID: 23946315). In another family, this variant was reported in an individual with A-T and moderate dyskinesia and in this individual’s mother with mild dystonia, both of whom also carry other pathogenic ATM variants in trans (PMID: 31407689). Additionally, this variant was found to be homozygous in an individual with A-T, was observed in trans with a pathogenic variant in an individual with isolated segmental dystonia, and has been observed as heterozygous in several individuals with breast cancer (PMID: 10330348, 27616075, 29470806, 30363071). However, it has also been observed in trans with a pathogenic variant in ATM in an individual not affected with A-T, indicating that this variant might not be causative of disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 181975). An experimental study using a lymphoblastoid cell line derived from an A-T affected individual has shown that this missense change can produce a defect in RNA splicing and loss of ATM protein (PMID: 10330348). 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.
Color Health, Inc RCV000159743 SCV000911078 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-30 criteria provided, single submitter clinical testing
Baylor Genetics RCV000167963 SCV001163272 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 Inc 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.
GeneReviews RCV000167963 SCV000328267 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Institute of Human Genetics, Klinikum rechts der Isar RCV000167963 SCV001150023 likely pathogenic Ataxia-telangiectasia syndrome 2019-06-13 no assertion criteria provided clinical testing
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.

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