VCV000140761.53 - ClinVar

NM_000051.4(ATM):c.2193C>T (p.Tyr731=)

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.

(24)

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.

Benign/Likely benign

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.2193C>T (p.Tyr731=)

Variation ID: 140761 Accession: VCV000140761.53

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108256283 (GRCh38) [ NCBI UCSC ] 11: 108127010 (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	Dec 6, 2016	Oct 20, 2024	May 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.2193C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Tyr731=	synonymous
NM_001351834.2:c.2193C>T	NP_001338763.1:p.Tyr731=	synonymous
NC_000011.10:g.108256283C>T
NC_000011.9:g.108127010C>T
NG_009830.1:g.38452C>T
LRG_135:g.38452C>T
LRG_135t1:c.2193C>T	LRG_135p1:p.Tyr731=

... more HGVS ... less HGVS

Protein change

Other names

NP_000042.3:p.Tyr731=

Canonical SPDI

NC_000011.10:108256282: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.

0.01837 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00387

Exome Aggregation Consortium (ExAC) 0.00509

The Genome Aggregation Database (gnomAD) 0.01543

Trans-Omics for Precision Medicine (TOPMed) 0.01680

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01746

1000 Genomes Project 0.01837

1000 Genomes Project 30x 0.01921

Links

ClinGen: CA163509 dbSNP: rs2229019 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	10851	17461

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	Benign (4)	criteria provided, multiple submitters, no conflicts	Mar 22, 2020	RCV000128878.15
Ataxia-telangiectasia syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000206183.27
not specified	Benign (7)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000679102.19
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Aug 24, 2023	RCV000710665.32
Malignant tumor of breast	Benign (1)	no assertion criteria provided	-	RCV001354816.10
Hereditary breast ovarian cancer syndrome	Benign (1)	criteria provided, single submitter	Apr 19, 2022	RCV002225412.9
Breast and/or ovarian cancer	Benign (1)	criteria provided, single submitter	Jul 2, 2021	RCV003149877.9
Familial cancer of breast	Benign (2)	criteria provided, multiple submitters, no conflicts	May 7, 2024	RCV003315858.9

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.
Benign (May 30, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000840924.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018
Benign (Apr 08, 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: SCV000682039.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Sep 14, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805512.1 First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000367033.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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: SCV002505206.1 First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022	Number of individuals with the variant: 11 Geographic origin: South Africa
Benign (Mar 22, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534221.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001945465.2 First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023
Benign (Jul 02, 2021)	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: SCV003837625.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Benign (Feb 01, 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: SCV000262430.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024
Benign (Aug 24, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001472244.4 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (Nov 25, 2014)	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: SCV000172735.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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)
Benign (May 07, 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: SCV005083868.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Likely benign (Feb 01, 2023)	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: SCV004133246.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: ATM: BP4, BP7 Number of individuals with the variant: 3
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016619.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (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: SCV004027171.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005231002.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922173.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001978370.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035870.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001461022.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001549522.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The ATM p.Tyr731Tyr variant was identified in 3 of 712 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer or leukemia (Mangone 2015, … (more) The ATM p.Tyr731Tyr variant was identified in 3 of 712 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer or leukemia (Mangone 2015, Gumy Pause 2003, Dâˆšâˆ‚rk 2001). The variant was also identified in dbSNP (ID: rs2229019) as "With other allele", in ClinVar (classified as 2x benign, 1x likely benign), Clinvitae (classified as 1x benign, 1x conflicting interpretations of pathogenicity), and Cosmic (1x as neutral). The variant was not identified in the MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1336 of 276956 (35 homozygous) chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1213 of 24022 chromosomes (freq: 0.05). The p.Tyr731Tyr variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less) Number of individuals with the variant: 1
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001905922.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951867.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (Jun 18, 2018)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000805211.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as 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:

The ATM p.Tyr731Tyr variant was identified in 3 of 712 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer or leukemia (Mangone 2015, Gumy Pause 2003, Dâˆšâˆ‚rk 2001). The variant was also identified in dbSNP (ID: rs2229019) as "With other allele", in ClinVar (classified as 2x benign, 1x likely benign), Clinvitae (classified as 1x benign, 1x conflicting interpretations of pathogenicity), and Cosmic (1x as neutral). The variant was not identified in the MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1336 of 276956 (35 homozygous) chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1213 of 24022 chromosomes (freq: 0.05). The p.Tyr731Tyr variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868

Text-mined citations for rs2229019 ...

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.2193C>T (p.Tyr731=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2229019 ...