VCV000142522.77 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(23)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(15); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 142522 Accession: VCV000142522.77

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108244795 (GRCh38) [ NCBI UCSC ] 11: 108115522 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 27, 2017	Nov 24, 2024	Nov 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.670A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Lys224Glu	missense
NM_001351834.2:c.670A>G	NP_001338763.1:p.Lys224Glu	missense
NC_000011.10:g.108244795A>G
NC_000011.9:g.108115522A>G
NG_009830.1:g.26964A>G
LRG_135:g.26964A>G
LRG_135t1:c.670A>G	LRG_135p1:p.Lys224Glu
	Q13315:p.Lys224Glu

... more HGVS ... less HGVS

Protein change

K224E

Other names

p.K224E:AAG>GAG
NM_000051.3(ATM):c.670A>G(p.Lys224Glu)

Canonical SPDI

NC_000011.10:108244794:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00006

The Genome Aggregation Database (gnomAD), exomes 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA294425 UniProtKB: Q13315#VAR_010801 dbSNP: rs145053092 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ATM		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	10850	17460

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jun 27, 2022	RCV000131698.21
Ataxia-telangiectasia syndrome	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000205199.20
not specified	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000211951.16
not provided	Conflicting interpretations of pathogenicity (10)	criteria provided, conflicting classifications	Nov 8, 2024	RCV000587384.49
Familial cancer of breast	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV001257492.9
ATM-related disorder	Uncertain significance (1)	no assertion criteria provided	Jan 22, 2024	RCV004551265.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jul 31, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: yes Allele origin: maternal	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481322.2 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Likely benign (Aug 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000682362.4 First in ClinVar: Feb 19, 2018 Last updated: Jun 19, 2021
Uncertain significance (Jun 14, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004222052.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (10) PubMed: 27616075‚ 23585524‚ 26689913‚ 19781682‚ 28779002‚ 31422574‚ 30303537‚ 25186627‚ 10817650‚ 36029002 Comment: In the published literature, this variant has been reported in an individual affected with ataxia-telangiectasia along with another pathogenic ATM variant (PMID: 10817650 (2000)), in … (more) In the published literature, this variant has been reported in an individual affected with ataxia-telangiectasia along with another pathogenic ATM variant (PMID: 10817650 (2000)), in multiple individuals with breast cancer (PMID: 19781682 (2009), 20305132 (2010), 26689913 (2015), 27616075 (2016), 28779002 (2017), and in an unaffected individual (PMID: 19781682 (2009)). 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. (less)
Uncertain significance (Jun 14, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV004229305.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (10) PubMed: 27616075‚ 23585524‚ 26689913‚ 19781682‚ 28779002‚ 31422574‚ 30303537‚ 25186627‚ 10817650‚ 36029002 Comment: 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 … (more) 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. (less)
Uncertain significance (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208121.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely benign (Sep 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001148400.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: ATM: BP4 Number of individuals with the variant: 2
Uncertain significance (Nov 08, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209679.19 First in ClinVar: Feb 24, 2015 Last updated: Nov 24, 2024	Comment: 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 … (more) 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) (less)
Uncertain significance (Jul 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000593495.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017
Uncertain significance (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803585.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Comment: 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 … (more) 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. (less)
Uncertain significance (Jan 04, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000703935.2 First in ClinVar: Dec 19, 2017 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Apr 24, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: no Allele origin: germline	Division of Medical Genetics, University of Washington Study: CSER_CHARM Accession: SCV001434303.1 First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020	Comment: 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 … (more) 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 (less) Indication for testing: Family history of breast and ovarian cancer
Uncertain significance (Jun 14, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002538415.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The ATM c.670A>G (p.K224E) has been reported in heterozygosity in numerous individuals with breast cancer, at least one individual with leukemia, and in numerous ethnically … (more) The ATM c.670A>G (p.K224E) has been reported in heterozygosity in numerous individuals with breast cancer, at least one individual with leukemia, and in numerous ethnically matched, unaffected controls (PMID: 33471991, 20305132, 25186627, 26689913, 19781682, 27616075, 26580448; OR= 0.5834 (95% CI: 0.0365 to 9.3321, z statistic: 0.381, P = 0.7032). This variant has also been identified as compound heterozygous in an individual with ataxia-telangiectasia (PMID: 10817650). It was observed in 21/128926 chromosomes, with no homozygotes, in the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 142522). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (8) PubMed: 33471991‚ 20305132‚ 25186627‚ 26689913‚ 19781682‚ 27616075‚ 26580448‚ 10817650
Uncertain significance (Mar 03, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694330.4 First in ClinVar: Mar 17, 2018 Last updated: May 13, 2023	Publications: PubMed (15) PubMed: 19781682‚ 20305132‚ 23585524‚ 25186627‚ 10817650‚ 26689913‚ 27616075‚ 26580448‚ 29659569‚ 30447919‚ 30303537‚ 31422574‚ 31920950‚ 33436325‚ 34262154 Comment: 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 … (more) 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. (less)
Likely benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259665.12 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (Jun 27, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186735.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 10817650‚ 19781682‚ 23585524‚ 26689913‚ 27616075‚ 29522266‚ 33436325 Comment: 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 … (more) 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jul 31, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714392.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 1
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010791.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004027141.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930593.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Uncertain significance (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001454842.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906420.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Uncertain significance (Jan 22, 2024)	no assertion criteria provided Method: clinical testing	ATM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805607.3 First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740622.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
click to load more click to collapse

Comment:

In the published literature, this variant has been reported in an individual affected with ataxia-telangiectasia along with another pathogenic ATM variant (PMID: 10817650 (2000)), in multiple individuals with breast cancer (PMID: 19781682 (2009), 20305132 (2010), 26689913 (2015), 27616075 (2016), 28779002 (2017), and in an unaffected individual (PMID: 19781682 (2009)). 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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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

Comment:

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.

Comment:

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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Rare germline ATM variants of uncertain significance in chronic lymphocytic leukaemia and other cancers.	Petrackova A	British journal of haematology	2022	PMID: 36029002
Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.	Dalmasso B	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 34262154
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.	Karlsson Q	European urology oncology	2021	PMID: 33436325
Single Molecule Molecular Inversion Probes for High Throughput Germline Screenings in Dystonia.	Pogoda M	Frontiers in neurology	2019	PMID: 31920950
Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort.	Kraemer D	Swiss medical weekly	2019	PMID: 31422574
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.	Girard E	International journal of cancer	2019	PMID: 30303537
Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: A systematic review and meta-analysis of gene-panel data.	van Marcke C	Critical reviews in oncology/hematology	2018	PMID: 30447919
Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer.	Paulo P	PLoS genetics	2018	PMID: 29659569
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.	Hauke J	Cancer medicine	2018	PMID: 29522266
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.	Decker B	Journal of medical genetics	2017	PMID: 28779002
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2.	Kraus C	International journal of cancer	2017	PMID: 27616075
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Germline Mutations in Predisposition Genes in Pediatric Cancer.	Zhang J	The New England journal of medicine	2015	PMID: 26580448
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.	Tung N	Cancer	2015	PMID: 25186627
ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin.	Navrkalova V	Haematologica	2013	PMID: 23585524
Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.	Bernstein JL	Journal of the National Cancer Institute	2010	PMID: 20305132
Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.	Tavtigian SV	American journal of human genetics	2009	PMID: 19781682
Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.	Li A	American journal of medical genetics	2000	PMID: 10817650
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM	-	-	-	-
click to load more click to collapse

Text-mined citations for rs145053092 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145053092 ...