VCV000181885.23 - ClinVar

NM_000051.4(ATM):c.6823A>G (p.Ile2275Val)

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.

Uncertain significance

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.6823A>G (p.Ile2275Val)

Variation ID: 181885 Accession: VCV000181885.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108326073 (GRCh38) [ NCBI UCSC ] 11: 108196800 (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	Jul 24, 2016	Oct 8, 2024	Sep 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.6823A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Ile2275Val	missense
NM_001330368.2:c.641-17002T>C		intron variant
NM_001351110.2:c.*38+9147T>C		intron variant
NM_001351834.2:c.6823A>G	NP_001338763.1:p.Ile2275Val	missense
NC_000011.10:g.108326073A>G
NC_000011.9:g.108196800A>G
NG_009830.1:g.108242A>G
NG_054724.1:g.148760T>C
LRG_135:g.108242A>G
LRG_135t1:c.6823A>G	LRG_135p1:p.Ile2275Val

... more HGVS ... less HGVS

Protein change

I2275V

Other names

p.I2275V:ATA>GTA

Canonical SPDI

NC_000011.10:108326072: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Links

ClinGen: CA298040 dbSNP: rs587779857 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
C11orf65	-	-	-	GRCh38 GRCh37	3	6592

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	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 11, 2023	RCV000219191.17
Ataxia-telangiectasia syndrome	Uncertain significance (2)	criteria provided, single submitter	Oct 27, 2022	RCV000456777.18
Familial cancer of breast	Uncertain significance (1)	criteria provided, single submitter	Sep 28, 2023	RCV003467220.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 13, 2022	RCV000589270.12
Ataxia-telangiectasia syndrome Familial cancer of breast	Uncertain significance (1)	criteria provided, single submitter	Oct 13, 2021	RCV002484994.8
ATM-related disorder	Uncertain significance (1)	no assertion criteria provided	Jun 6, 2024	RCV004724945.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Mar 17, 2023	RCV003226221.8

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 (Oct 27, 2022)	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: SCV000546845.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2275 of the ATM protein (p.Ile2275Val). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2275 of the ATM protein (p.Ile2275Val). This variant is present in population databases (rs587779857, gnomAD 0.0009%). 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: 181885). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207114.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Dec 13, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209634.14 First in ClinVar: Feb 24, 2015 Last updated: Dec 24, 2022	Comment: Observed in cases as well as controls in a breast cancer case-control study (Dorling et al., 2021); In silico analysis supports that this missense variant … (more) Observed in cases as well as controls in a breast cancer case-control study (Dorling et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23532176, 33471991) (less)
Uncertain significance (Oct 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002796939.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Mar 17, 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: SCV000694334.2 First in ClinVar: Mar 17, 2018 Last updated: May 13, 2023	Publications: PubMed (1) PubMed: 28652578 Comment: Variant summary: ATM c.6823A>G (p.Ile2275Val) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. … (more) Variant summary: ATM c.6823A>G (p.Ile2275Val) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 4e-06 in 251100 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6823A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Sep 20, 2021)	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: SCV000911406.3 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Comment: This missense variant replaces isoleucine with valine at codon 2275 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces isoleucine with valine at codon 2275 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 11, 2023)	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: SCV000275025.8 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 33471991 Comment: The p.I2275V variant (also known as c.6823A>G), located in coding exon 46 of the ATM gene, results from an A to G substitution at nucleotide … (more) The p.I2275V variant (also known as c.6823A>G), located in coding exon 46 of the ATM gene, results from an A to G substitution at nucleotide position 6823. The isoleucine at codon 2275 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jun 06, 2024)	no assertion criteria provided Method: clinical testing	ATM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005339665.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The ATM c.6823A>G variant is predicted to result in the amino acid substitution p.Ile2275Val. This variant has been reported both in individuals with breast cancer … (more) The ATM c.6823A>G variant is predicted to result in the amino acid substitution p.Ile2275Val. This variant has been reported both in individuals with breast cancer and in controls in a large cohort study of women with breast cancer and controls (Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181885/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458454.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2275 of the ATM protein (p.Ile2275Val). This variant is present in population databases (rs587779857, gnomAD 0.0009%). 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: 181885). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Observed in cases as well as controls in a breast cancer case-control study (Dorling et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23532176, 33471991)

Comment:

Variant summary: ATM c.6823A>G (p.Ile2275Val) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 4e-06 in 251100 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6823A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This missense variant replaces isoleucine with valine at codon 2275 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The p.I2275V variant (also known as c.6823A>G), located in coding exon 46 of the ATM gene, results from an A to G substitution at nucleotide position 6823. The isoleucine at codon 2275 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

The ATM c.6823A>G variant is predicted to result in the amino acid substitution p.Ile2275Val. This variant has been reported both in individuals with breast cancer and in controls in a large cohort study of women with breast cancer and controls (Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181885/). 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
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 are associated with chronic lymphocytic leukemia.	Tiao G	Leukemia	2017	PMID: 28652578

Text-mined citations for rs587779857 ...

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.6823A>G (p.Ile2275Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587779857 ...