VCV000187077.50 - ClinVar

NM_000051.4(ATM):c.7816A>G (p.Ile2606Val)

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.

(13)

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(11); Likely benign(1)

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.7816A>G (p.Ile2606Val)

Variation ID: 187077 Accession: VCV000187077.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108332789 (GRCh38) [ NCBI UCSC ] 11: 108203516 (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 30, 2017	Oct 20, 2024	Mar 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.7816A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Ile2606Val	missense
NM_001330368.2:c.641-23718T>C		intron variant
NM_001351110.2:c.*38+2431T>C		intron variant
NM_001351834.2:c.7816A>G	NP_001338763.1:p.Ile2606Val	missense
NC_000011.10:g.108332789A>G
NC_000011.9:g.108203516A>G
NG_009830.1:g.114958A>G
NG_054724.1:g.142044T>C
LRG_135:g.114958A>G
LRG_135t1:c.7816A>G	LRG_135p1:p.Ile2606Val

... more HGVS ... less HGVS

Protein change

I2606V

Other names

Canonical SPDI

NC_000011.10:108332788: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA196681 dbSNP: rs376824528 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	Oct 31, 2023	RCV000166765.19
Ataxia-telangiectasia syndrome	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000197716.23
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Apr 24, 2023	RCV000513206.33
not specified	Uncertain significance (1)	criteria provided, single submitter	May 3, 2020	RCV000625763.12
Familial cancer of breast	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Mar 30, 2024	RCV002265647.12
Ataxia-telangiectasia syndrome Familial cancer of breast	Uncertain significance (1)	criteria provided, single submitter	Jul 2, 2021	RCV002485035.8

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 (May 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000746305.2 First in ClinVar: Apr 29, 2018 Last updated: May 31, 2020
Uncertain significance (Oct 31, 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: SCV000217578.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 25186627‚ 35980532 Comment: The p.I2606V variant (also known as c.7816A>G), located in coding exon 52 of the ATM gene, results from an A to G substitution at nucleotide … (more) The p.I2606V variant (also known as c.7816A>G), located in coding exon 52 of the ATM gene, results from an A to G substitution at nucleotide position 7816. The isoleucine at codon 2606 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in individuals with a personal and/or family history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Pereira JZ et al. Mol Biol Rep, 2022 Oct;49:9509-9520). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207706.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Sep 08, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805619.1 First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018
Uncertain significance (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838598.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Uncertain significance (Apr 24, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000564661.6 First in ClinVar: Apr 29, 2017 Last updated: May 06, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a minimal effect on splicing compared to controls (Dragos et al., 2022); Observed in individuals with a personal and/or family history of breast, ovarian, prostate, and other cancers (Tung et al., 2015; Karlsson et al., 2021; Andrikopoulou et al., 2022; Dragos et al., 2022); This variant is associated with the following publications: (PMID: 23338612, 25428177, 33436325, 35806449, 36531003, 25186627) (less)
Likely benign (Mar 31, 2023)	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: SCV004019654.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	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)
Uncertain significance (Jan 31, 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: SCV000254152.11 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 28492532‚ 33436325 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2606 of the ATM protein (p.Ile2606Val). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2606 of the ATM protein (p.Ile2606Val). This variant is present in population databases (rs376824528, gnomAD 0.004%). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 187077). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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 (Jan 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: SCV000608619.25 First in ClinVar: Oct 30, 2017 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Uncertain significance (May 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV002548546.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Publications: PubMed (1) PubMed: 35806449 Comment: ATM:c.7816A>G variant is predicted to create a de novo donor ss 28 bp upstream of natural splice site. Functional RNA study has shown that the … (more) ATM:c.7816A>G variant is predicted to create a de novo donor ss 28 bp upstream of natural splice site. Functional RNA study has shown that the variant may cause minimally expressed whole exon 53 skipping (PMID: 35806449). Missense in silico tools predict that the variant does not have an impact on protein function (REVEL 0.26). Therefore the variant was classified as variant of uncertain significance (ACMG/AMP: PP3) (less)
Uncertain significance (Jul 02, 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: SCV002787210.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Dec 21, 2022)	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: SCV000902970.4 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 25186627‚ 33436325‚ 35806449‚ 36531003 Comment: This missense variant replaces isoleucine with valine at codon 2606 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 2606 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). RNA studies have showed this variant causes a minor increase in exon 53 skipping (PMID: 35806449). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 35806449), ovarian cancer (PMID: 36531003), or prostate cancer (PMID: 33436325). In a large international case-control study, this variant was reported in 5/60461 breast cancer cases and 5/53456 controls (OR=0.884, 95%CI 0.256 to 3.054, p-value=1; PMID: 33471991). This variant has also been identified in 4/250604 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 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462595.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

The p.I2606V variant (also known as c.7816A>G), located in coding exon 52 of the ATM gene, results from an A to G substitution at nucleotide position 7816. The isoleucine at codon 2606 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in individuals with a personal and/or family history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Pereira JZ et al. Mol Biol Rep, 2022 Oct;49:9509-9520). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a minimal effect on splicing compared to controls (Dragos et al., 2022); Observed in individuals with a personal and/or family history of breast, ovarian, prostate, and other cancers (Tung et al., 2015; Karlsson et al., 2021; Andrikopoulou et al., 2022; Dragos et al., 2022); This variant is associated with the following publications: (PMID: 23338612, 25428177, 33436325, 35806449, 36531003, 25186627)

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2606 of the ATM protein (p.Ile2606Val). This variant is present in population databases (rs376824528, gnomAD 0.004%). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 187077). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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:

ATM:c.7816A>G variant is predicted to create a de novo donor ss 28 bp upstream of natural splice site. Functional RNA study has shown that the variant may cause minimally expressed whole exon 53 skipping (PMID: 35806449). Missense in silico tools predict that the variant does not have an impact on protein function (REVEL 0.26). Therefore the variant was classified as variant of uncertain significance (ACMG/AMP: PP3)

Comment:

This missense variant replaces isoleucine with valine at codon 2606 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). RNA studies have showed this variant causes a minor increase in exon 53 skipping (PMID: 35806449). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 35806449), ovarian cancer (PMID: 36531003), or prostate cancer (PMID: 33436325). In a large international case-control study, this variant was reported in 5/60461 breast cancer cases and 5/53456 controls (OR=0.884, 95%CI 0.256 to 3.054, p-value=1; PMID: 33471991). This variant has also been identified in 4/250604 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.

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 and somatic variants in ovarian carcinoma: A next-generation sequencing (NGS) analysis.	Andrikopoulou A	Frontiers in oncology	2022	PMID: 36531003
Frequency of germline genetic variants in women with a personal or family history of breast cancer from Brazil.	Pereira JZ	Molecular biology reports	2022	PMID: 35980532
Identification of Spliceogenic Variants beyond Canonical GT-AG Splice Sites in Hereditary Cancer Genes.	Dragoš VŠ	International journal of molecular sciences	2022	PMID: 35806449
Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.	Karlsson Q	European urology oncology	2021	PMID: 33436325
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

Text-mined citations for rs376824528 ...

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.7816A>G (p.Ile2606Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs376824528 ...