VCV000140915.47 - ClinVar

NM_000051.4(ATM):c.749G>A (p.Arg250Gln)

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.

(17)

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(5); Likely benign(10)

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.749G>A (p.Arg250Gln)

Variation ID: 140915 Accession: VCV000140915.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108244874 (GRCh38) [ NCBI UCSC ] 11: 108115601 (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	Apr 9, 2018	Dec 22, 2024	Apr 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.749G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Arg250Gln	missense
NM_001351834.2:c.749G>A	NP_001338763.1:p.Arg250Gln	missense
NC_000011.10:g.108244874G>A
NC_000011.9:g.108115601G>A
NG_009830.1:g.27043G>A
LRG_135:g.27043G>A
LRG_135t1:c.749G>A	LRG_135p1:p.Arg250Gln
	Q13315:p.Arg250Gln

... more HGVS ... less HGVS

Protein change

R250Q

Other names

p.R250Q:CGA>CAA
NP_000042.3:p.Arg250Gln

Canonical SPDI

NC_000011.10:108244873:G:A

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) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00005

The Genome Aggregation Database (gnomAD) 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00008

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA293997 UniProtKB: Q13315#VAR_041547 dbSNP: rs56123940 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	10978	17671

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 (4)	criteria provided, conflicting classifications	Dec 9, 2020	RCV000129173.15
Ataxia-telangiectasia syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 29, 2024	RCV000204231.24
not specified	Likely benign (1)	criteria provided, single submitter	Jul 17, 2021	RCV000211952.8
Familial cancer of breast	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Apr 23, 2024	RCV001257469.4
Breast and/or ovarian cancer	Uncertain significance (1)	criteria provided, single submitter	May 24, 2019	RCV001798434.4
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Oct 1, 2022	RCV001704053.20
Hereditary breast ovarian cancer syndrome	Likely benign (1)	criteria provided, single submitter	Apr 19, 2022	RCV002225424.3
Hereditary cancer	Likely benign (1)	criteria provided, single submitter	Jan 23, 2024	RCV003492586.1

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.
Likely benign (Aug 05, 2015)	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: SCV000910702.1 First in ClinVar: May 19, 2019 Last updated: May 19, 2019
Likely benign (Jul 17, 2021)	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: SCV001360414.2 First in ClinVar: Jun 22, 2020 Last updated: Aug 07, 2021	Publications: PubMed (10) PubMed: 17344846‚ 23555315‚ 19404735‚ 25186627‚ 26155992‚ 28652578‚ 30256826‚ 31206626‚ 31159747‚ 33606809 Comment: Variant summary: ATM c.749G>A (p.Arg250Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more) Variant summary: ATM c.749G>A (p.Arg250Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250992 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.8e-05 vs 0.004), allowing no conclusion about variant significance. However, the presence of a homozygous occurrence in healthy controls suggests that the variant has a neutral impact. c.749G>A has been reported in the literature in settings of multigene panel testing in individuals affected with various cancer phenotypes without strong evidence for causality (examples-Grennman_2007, LaPaglia_2009, Haiman_2013, Tung_2015, Muller_2015, Tiao_2017, Martin-Moales_2018, Tsaousis_2019, Weitzel_2019, Sandoval_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=4). Based on the emerging majority consensus among peers and the evidence outlined above, the variant was re-classified as likely benign. (less)
Likely benign (Oct 28, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209681.13 First in ClinVar: Feb 24, 2015 Last updated: Apr 09, 2018	Comment: This variant is associated with the following publications: (PMID: 19404735, 17344846, 22529920, 28779002, 31159747)
Uncertain significance (May 15, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000799869.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018
Uncertain significance (Aug 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	GeneKor MSA Accession: SCV000821872.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018
Uncertain significance (Oct 04, 2019)	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: SCV001434275.1 First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020	Comment: This variant has been reported in the literature in an individual with breast cancer (Paglia 2010). This variant has an overall allele frequency of 0.00005 … (more) This variant has been reported in the literature in an individual with breast cancer (Paglia 2010). This variant has an overall allele frequency of 0.00005 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 (less) Indication for testing: Family history of breast cancer Secondary finding: yes
Uncertain significance (May 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV002042895.1 First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021
Likely benign (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State Accession: SCV002505028.1 First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022	Number of individuals with the variant: 1 Geographic origin: South Africa
Likely benign (Dec 09, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002538038.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Uncertain significance (Jul 20, 2021)	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: SCV002774770.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (11) PubMed: 28779002‚ 19404735‚ 17344846‚ 22529920‚ 31159747‚ 33471991‚ 30256826‚ 28652578‚ 26155992‚ 25186627‚ 23555315
Likely benign (Jan 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838477.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 04, 2024
Likely benign (Jan 29, 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: SCV000259752.12 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (Sep 29, 2018)	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: SCV000183906.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Apr 23, 2024)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV005083937.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 25085752 Comment: This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more) This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
Likely benign (Oct 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: SCV002821661.15 First in ClinVar: Jan 21, 2023 Last updated: Dec 22, 2024	Comment: ATM: BP4, BS2 Number of individuals with the variant: 1
Likely benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001454847.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002075271.1 First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022	Comment: Variant interpreted as Uncertain significance and reported on 08-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more) Variant interpreted as Uncertain significance and reported on 08-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Obesity (present) , Type 2 diabetes mellitus (present) , Hyperthyroidism (present) , Abnormality of the parathyroid physiology (present) , Abnormality of eye movement (present) , … (more) Obesity (present) , Type 2 diabetes mellitus (present) , Hyperthyroidism (present) , Abnormality of the parathyroid physiology (present) , Abnormality of eye movement (present) , Myopia (present) , Hypermetropia (present) , Ptosis (present) , Hearing impairment (present) , Tinnitus (present) , Bipolar affective disorder (present) , Motor stereotypies (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Short attention span (present) , Thickened skin (present) , Cutis laxa (present) , Increased susceptibility to fractures (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormal morphology of the pelvis musculature (present) , Cardiac arrhythmia (present) , Abnormal intestine morphology (present) , Autoimmunity (present) , Recurrent infections (present) , Gingivitis (present) (less) Indication for testing: Presymptomatic Age: 40-49 years Sex: female Ethnicity/Population group: Caucasians Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2016-08-11 Testing laboratory interpretation: Uncertain significance
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Comment:

Variant summary: ATM c.749G>A (p.Arg250Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250992 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.8e-05 vs 0.004), allowing no conclusion about variant significance. However, the presence of a homozygous occurrence in healthy controls suggests that the variant has a neutral impact. c.749G>A has been reported in the literature in settings of multigene panel testing in individuals affected with various cancer phenotypes without strong evidence for causality (examples-Grennman_2007, LaPaglia_2009, Haiman_2013, Tung_2015, Muller_2015, Tiao_2017, Martin-Moales_2018, Tsaousis_2019, Weitzel_2019, Sandoval_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=4). Based on the emerging majority consensus among peers and the evidence outlined above, the variant was re-classified as likely benign.

Comment:

This variant has been reported in the literature in an individual with breast cancer (Paglia 2010). This variant has an overall allele frequency of 0.00005 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Variant interpreted as Uncertain significance and reported on 08-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis.	Sandoval RL	PloS one	2021	PMID: 33606809
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
Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.	Weitzel JN	Cancer	2019	PMID: 31206626
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.	Martin-Morales L	PloS one	2018	PMID: 30256826
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
Rare germline variants in ATM are associated with chronic lymphocytic leukemia.	Tiao G	Leukemia	2017	PMID: 28652578
Genetic profiles of cervical tumors by high-throughput sequencing for personalized medical care.	Muller E	Cancer medicine	2015	PMID: 26155992
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
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.	Pruss D	Breast cancer research and treatment	2014	PMID: 25085752
Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.	Haiman CA	PLoS genetics	2013	PMID: 23555315
Computational refinement of functional single nucleotide polymorphisms associated with ATM gene.	George Priya Doss C	PloS one	2012	PMID: 22529920
ATM germline mutations in women with familial breast cancer and a relative with haematological malignancy.	Paglia LL	Breast cancer research and treatment	2010	PMID: 19404735
Patterns of somatic mutation in human cancer genomes.	Greenman C	Nature	2007	PMID: 17344846
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Text-mined citations for rs56123940 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.749G>A (p.Arg250Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs56123940 ...