VCV000231933.21 - ClinVar

NM_000051.4(ATM):c.2023C>T (p.Gln675Ter)

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.

(9)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000051.4(ATM):c.2023C>T (p.Gln675Ter)

Variation ID: 231933 Accession: VCV000231933.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108253938 (GRCh38) [ NCBI UCSC ] 11: 108124665 (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	Oct 9, 2016	Jan 19, 2025	Jun 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.2023C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Gln675Ter	nonsense
NM_001351834.2:c.2023C>T	NP_001338763.1:p.Gln675Ter	nonsense
NC_000011.10:g.108253938C>T
NC_000011.9:g.108124665C>T
NG_009830.1:g.36107C>T
LRG_135:g.36107C>T
LRG_135t1:c.2023C>T	LRG_135p1:p.Gln675Ter

... more HGVS ... less HGVS

Protein change

Q675*

Other names

Canonical SPDI

NC_000011.10:108253937:C:T

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA6264916 dbSNP: rs777849257 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	10982	17684

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	Pathogenic (1)	criteria provided, single submitter	Jun 11, 2024	RCV000215540.7
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 12, 2024	RCV000255863.6
Ataxia-telangiectasia syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 17, 2023	RCV000411314.11
Familial cancer of breast	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 5, 2024	RCV001293971.4
Malignant tumor of urinary bladder	Pathogenic (1)	no assertion criteria provided	-	RCV003332147.1

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.
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447816.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cerebellar ataxia (present) Sex: female
Likely pathogenic (Nov 01, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487230.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022
Pathogenic (Nov 17, 2023)	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: SCV000829660.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 28492532‚ 23807571‚ 25614872 Comment: This sequence change creates a premature translational stop signal (p.Gln675) in the ATM gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gln675) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs777849257, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 231933). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 17, 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: SCV004933426.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Mar 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001482694.2 First in ClinVar: Mar 07, 2021 Last updated: Jun 17, 2024
Pathogenic (Jun 11, 2024)	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: SCV000275934.9 First in ClinVar: May 29, 2016 Last updated: Aug 11, 2024	Comment: The p.Q675* pathogenic mutation (also known as c.2023C>T), located in coding exon 12 of the ATM gene, results from a C to T substitution at … (more) The p.Q675* pathogenic mutation (also known as c.2023C>T), located in coding exon 12 of the ATM gene, results from a C to T substitution at nucleotide position 2023. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Apr 16, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322534.8 First in ClinVar: Oct 09, 2016 Last updated: Sep 29, 2024	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with breast or prostate cancer (PMID: 36446039, 32832836, 29922827); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 36446039, 32832836, 29922827, 32427313) (less)
pathogenic (Jun 12, 2024)	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: SCV005625710.1 First in ClinVar: Jan 19, 2025 Last updated: Jan 19, 2025	Publications: PubMed (5) PubMed: 32832836‚ 29922827‚ 32427313‚ 36446039‚ 33471991 Comment: The ATM c.2023C>T (p.Gln675) variant causes the premature termination of ATM protein synthesis. This variant has been reported in the published literature in individuals with … (more) The ATM c.2023C>T (p.Gln675) variant causes the premature termination of ATM protein synthesis. This variant has been reported in the published literature in individuals with breast (PMID: 32427313 (2020)), prostate (PMIDs: 32832836 (2020) and 36446039 (2022)), and pancreatic cancers (PMID: 29922827 (2018)). In a large scale breast cancer association study, this variant was reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: research	Malignant tumor of urinary bladder Affected status: yes Allele origin: somatic	Laboratory of Urology, Hospital Clinic de Barcelona Accession: SCV004040581.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023

Comment:

This sequence change creates a premature translational stop signal (p.Gln675*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs777849257, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 231933). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Q675* pathogenic mutation (also known as c.2023C>T), located in coding exon 12 of the ATM gene, results from a C to T substitution at nucleotide position 2023. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with breast or prostate cancer (PMID: 36446039, 32832836, 29922827); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 36446039, 32832836, 29922827, 32427313)

Comment:

The ATM c.2023C>T (p.Gln675*) variant causes the premature termination of ATM protein synthesis. This variant has been reported in the published literature in individuals with breast (PMID: 32427313 (2020)), prostate (PMIDs: 32832836 (2020) and 36446039 (2022)), and pancreatic cancers (PMID: 29922827 (2018)). In a large scale breast cancer association study, this variant was reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). Based on the available information, this variant is classified as pathogenic.

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 Variants in DNA Damage Repair Genes and HOXB13 Among Black Patients With Early-Onset Prostate Cancer.	Trendowski MR	JCO precision oncology	2022	PMID: 36446039
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 Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.	Matejcic M	JCO precision oncology	2020	PMID: 32832836
Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women.	Palmer JR	Journal of the National Cancer Institute	2020	PMID: 32427313
Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.	Hu C	JAMA	2018	PMID: 29922827
Ten new ATM alterations in Polish patients with ataxia-telangiectasia.	Podralska MJ	Molecular genetics & genomic medicine	2014	PMID: 25614872
Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.	Huang Y	Neuromolecular medicine	2013	PMID: 23807571

Text-mined citations for rs777849257 ...

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 19, 2025

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.2023C>T (p.Gln675Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777849257 ...