VCV000133630.46 - ClinVar

NM_000051.4(ATM):c.6437G>C (p.Ser2146Thr)

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(1); Benign(13); 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.6437G>C (p.Ser2146Thr)

Variation ID: 133630 Accession: VCV000133630.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108320043 (GRCh38) [ NCBI UCSC ] 11: 108190770 (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	Jun 9, 2014	Sep 29, 2024	Jun 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.6437G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Ser2146Thr	missense
NM_001330368.2:c.641-10972C>G		intron variant
NM_001351110.2:c.*39-10972C>G		intron variant
NM_001351834.2:c.6437G>C	NP_001338763.1:p.Ser2146Thr	missense
NC_000011.10:g.108320043G>C
NC_000011.9:g.108190770G>C
NG_009830.1:g.102212G>C
NG_054724.1:g.154790C>G
LRG_135:g.102212G>C
LRG_135t1:c.6437G>C	LRG_135p1:p.Ser2146Thr

... more HGVS ... less HGVS

Protein change

S2146T

Other names

p.S2146T:AGT>ACT
NP_000042.3:p.Ser2146Thr

Canonical SPDI

NC_000011.10:108320042:G:C

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.

0.00240 (C)

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

1000 Genomes Project 0.00240

1000 Genomes Project 30x 0.00250

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00393

The Genome Aggregation Database (gnomAD) 0.00424

Trans-Omics for Precision Medicine (TOPMed) 0.00494

The Genome Aggregation Database (gnomAD), exomes 0.00096

Exome Aggregation Consortium (ExAC) 0.00130

Links

ClinGen: CA157159 dbSNP: rs56815840 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	10839	17439
C11orf65	-	-	-	GRCh38 GRCh37	3	6582

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.
not specified	Benign (9)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000120154.27
Hereditary cancer-predisposing syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	May 11, 2022	RCV000131611.18
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Oct 16, 2023	RCV000710676.23
Ataxia-telangiectasia syndrome	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001080465.21
Hereditary breast ovarian cancer syndrome	Likely benign (1)	criteria provided, single submitter	Apr 19, 2022	RCV002225364.9
Familial cancer of breast	Benign (2)	criteria provided, multiple submitters, no conflicts	Jun 6, 2024	RCV003315729.9
Breast and/or ovarian cancer	Uncertain significance (1)	criteria provided, single submitter	Sep 21, 2021	RCV003149825.9

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 (Dec 16, 2014)	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: SCV000682338.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (May 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV002819211.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023
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: SCV000262364.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024
Benign (Nov 21, 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: SCV000186627.8 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 (Oct 11, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167098.11 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Oct 03, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805599.1 First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018
Benign (Jun 14, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000840952.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018	Publications: PubMed (4) PubMed: 17333338‚ 24728327‚ 12917204‚ 23555315
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: SCV002504752.1 First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022	Number of individuals with the variant: 6 Geographic origin: South Africa
Uncertain significance (Sep 21, 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: SCV003837858.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
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: SCV004024708.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Benign (Dec 29, 2022)	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: SCV004222037.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (5) PubMed: 33471991‚ 17333338‚ 24728327‚ 12917204‚ 23555315
Benign (Oct 16, 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: SCV000885039.3 First in ClinVar: Feb 17, 2019 Last updated: Feb 20, 2024
Likely 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: SCV005218569.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Apr 28, 2017)	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: SCV001264709.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jan 25, 2018)	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: SCV000593488.2 First in ClinVar: Jun 09, 2014 Last updated: Jun 12, 2020
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: SCV004016697.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Jun 06, 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: SCV005084068.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence … (more) This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001551783.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The ATM p.Ser2146Thr variant was not identified in the literature nor was it identified in the COGR, Cosmic, or ATM-LOVD databases. The variant was identified … (more) The ATM p.Ser2146Thr variant was not identified in the literature nor was it identified in the COGR, Cosmic, or ATM-LOVD databases. The variant was identified in dbSNP (ID: rs56815840) as "With other allele ", ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics; as likely benign by one clinical laboratory), MutDB, and in LOVD 3.0 (1x as benign). The variant was identified in control databases in 347 of 275004 chromosomes (3 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 300 of 24016 chromosomes (freq: 0.013), Other in 11 of 6442 chromosomes (freq: 0.002), Latino in 33 of 34386 chromosomes (freq: 0.0009), European in 3 of 124640 chromosomes (freq: 0.00002), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ser2146 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968988.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457416.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809619.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 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: SCV001954820.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084295.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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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:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

The ATM p.Ser2146Thr variant was not identified in the literature nor was it identified in the COGR, Cosmic, or ATM-LOVD databases. The variant was identified in dbSNP (ID: rs56815840) as "With other allele ", ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics; as likely benign by one clinical laboratory), MutDB, and in LOVD 3.0 (1x as benign). The variant was identified in control databases in 347 of 275004 chromosomes (3 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 300 of 24016 chromosomes (freq: 0.013), Other in 11 of 6442 chromosomes (freq: 0.002), Latino in 33 of 34386 chromosomes (freq: 0.0009), European in 3 of 124640 chromosomes (freq: 0.00002), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ser2146 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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
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
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
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
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
Screening for ATM sequence alterations in African-American women diagnosed with breast cancer.	Hirsch AE	Breast cancer research and treatment	2008	PMID: 17333338
The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort.	Bretsky P	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2003	PMID: 12917204

Text-mined citations for rs56815840 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.6437G>C (p.Ser2146Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs56815840 ...