rs202206540

Variant names:

• chr11-108316069-G-A
• rs202206540
• NM_000051.4:c.6154G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108316069-G-A
• chr11-108316069-G-C
• chr11-108316069-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_000051.4(ATM):​c.6154G>A​(p.Glu2052Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,614,038 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2052G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:6 O:1
• Conservation: PhyloP100: 6.82
• Publications: 16 publications found

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 11-108316069-G-A is Pathogenic according to our data. Variant chr11-108316069-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181975.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.6154G>A	p.Glu2052Lys	missense_variant	Exon 42 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6154G>A	p.Glu2052Lys	missense_variant	Exon 42 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251398 AF XY: 0.0000883

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461864 Hom.: 1 Cov.: 32 AF XY: 0.0000481 AC XY: 35 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74398

African (AFR) AF: 0.0000241 AC: 1 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000142 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15 Uncertain:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4 Uncertain:1 Other:1

Feb 23, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Aug 12, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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, 38854973). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. 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 (internal data). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 181975). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Jun 13, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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not provided Pathogenic:2 Uncertain:3

Oct 28, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Oct 28, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Sep 16, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Apr 28, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Familial cancer of breast Pathogenic:3 Uncertain:1

Jun 06, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 03, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS4_MOD, PP3 -

Feb 29, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Hereditary cancer-predisposing syndrome Pathogenic:3

Mar 13, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 2052 in the FAT domain of the ATM protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. An RNA study suggested that this variant may impact splicing but the results were inconclusive (PMID: 10330348). More recent RNA studies indicated that this variant does not impact splicing (communication with an external laboratory; ClinVar SCV000218611.14). Computational prediction tools suggest that this variant may not impact protein structure and function. This variant has been observed in the homozygous state and the compound heterozygous state with other pathogenic ATM variants in individuals and families affected with a mild form of autosomal-recessive ataxia-telangiectasia and/or dystonia (PMID: 10330348, 23946315, 30363071, 31407689, 35154108, 38854973), indicating that this variant contributes to disease. Lymphoblastoid cell lines derived from two of these individuals, siblings affected with variant ataxia-telangiectasia, showed reduced levels of ATM expression and kinase activity (PMID: 35154108). This variant has been reported in heterozygous individuals affected with breast cancer and/or ovarian cancer (PMID: 27616075, 29470806, 30128536, 31125277, 32125938, 32860008, 33919281, 35734982, 38118367, 38854973; DOI: 10.14744/ejmo.2022.88057), prostate cancer (PMID: 32832836), and colorectal cancer (PMID: 29470806). This variant has been identified in 16/282788 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. Since this variant has been strongly associated with a mild form of an autosomal-recessive disease, it appears to be hypomorphic and may display reduced cancer penetrance relative to typical pathogenic ATM variants. Medical management of heterozygous individuals should be considered based on the individual's personal and family history. -

Feb 03, 2022

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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Aug 05, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 diagnosed 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; Jin B et al. Neurol Genet, 2024 Apr;10:e200141), 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. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

Jan 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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ATM-related disorder Pathogenic:1

Jun 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.6154G>A variant is predicted to result in the amino acid substitution p.Glu2052Lys. This variant has been reported in the homozygous state in an individual with ataxia telangiectasia, and RNA studies suggest that this variant may disrupt mRNA splicing (Table 2, Teraoka et al. 1999. PubMed ID: 10330348). This variant has been reported in trans with another pathogenic variant in individuals and families affected with dystonia and clinical features consistent with variant ataxia telangiectasia (Blanchard-Rohner G et al. 2022. PubMed ID: 35154108; Charlesworth G et al. 2013. PubMed ID: 23946315; Necpál J et al. 2017. PubMed ID: 30363071). This variant has also been reported in multiple individuals with breast, ovarian, and colorectal cancers (see for example, Table S2, Kraus et al. 2017. PubMed ID: 27616075; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541; Table S2, Hampel et al. 2018. PubMed ID: 29596542). Experimental studies in patient-derived lymphoblastic cell lines suggest that this variant may reduce but does not completely disrupt protein function (Blanchard-Rohner G et al. 2022. PubMed ID: 35154108). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD and it has classifications ranging from pathogenic to uncertain by other institutions in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181975/). This variant is interpreted as likely pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Sep 10, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ClinGen ACMG ATM v1.3.0 criteria we chose these criteria: PS3 (medium pathogenic): Blanchard-Rohner, 2022 (PMID: 35154108): Lymphoblastoid cell lines derived from two individuals affected with variant ataxia-telangiectasia (diagnosed in young adulthood as their phenotype was much milder), showed reduced levels of ATM expression and ATM activity, while some residual ATM kinase activity still remained. Functional studies performed by this group revealed absence of ATM protein by Western blotting and ATM transcripts with missing exon 44 (PMID: 10330348), PM3 (strong pathogenic): Observed with a second pathogenic ATM variant in trans in several individuals who had a milder phenotype of ataxia telangiectasia (e.g. Charlesworth 2013; PMID: 23946315); Patients typically showed 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 (Schon 2019; PMID: 30549301). Invitae: 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 (Accession-ID: SCV000218611.13). , BP4 (supporting benign): REVEL 0.21 -

Malignant tumor of breast Uncertain:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		6.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.21
Sift	Benign	0.053	T;T
Sift4G	Benign	0.071	T;T
Polyphen		0.99	D;D
Vest4		0.56
MutPred		0.40		Gain of ubiquitination at E2052 (P = 0.0155);Gain of ubiquitination at E2052 (P = 0.0155);
MVP		0.97
MPC		0.52
ClinPred		0.30	T
GERP RS		5.3
Varity_R		0.56
gMVP		0.51
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202206540; hg19: chr11-108186796; COSMIC: COSV53773430;