VCV000854458.21 - ClinVar

NM_000051.4(ATM):c.7397C>A (p.Ala2466Glu)

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.

(6)

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
Likely pathogenic(3); Uncertain significance(2)

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.7397C>A (p.Ala2466Glu)

Variation ID: 854458 Accession: VCV000854458.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108330303 (GRCh38) [ NCBI UCSC ] 11: 108201030 (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	Apr 15, 2020	Jun 17, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.7397C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Ala2466Glu	missense
NM_001330368.2:c.641-21232G>T		intron variant
NM_001351110.2:c.*38+4917G>T		intron variant
NM_001351834.2:c.7397C>A	NP_001338763.1:p.Ala2466Glu	missense
NC_000011.10:g.108330303C>A
NC_000011.9:g.108201030C>A
NG_009830.1:g.112472C>A
NG_054724.1:g.144530G>T
LRG_135:g.112472C>A
LRG_135t1:c.7397C>A	LRG_135p1:p.Ala2466Glu

... more HGVS ... less HGVS

Protein change

A2466E

Other names

Canonical SPDI

NC_000011.10:108330302:C:A

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 0.00001

Links

dbSNP: rs1324075885 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.
Ataxia-telangiectasia syndrome	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Sep 25, 2022	RCV001059517.17
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Feb 17, 2023	RCV003160479.9
Familial cancer of breast	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV003467801.3

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 (Sep 25, 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: SCV001224143.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023	Publications: PubMed (3) PubMed: 26896183‚ 31429931‚ 33376610 Comment: This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2466 of the ATM protein … (more) This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2466 of the ATM protein (p.Ala2466Glu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 26896183, 31429931, 33376610; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 854458). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047768.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The missense variant in c.7397C>A(p.Ala2466Glu) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. … (more) The missense variant in c.7397C>A(p.Ala2466Glu) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala2466Glu variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0008% in gnomAD database. This variant has been reported to the ClinVar database as Variant of Uncertain Significance (VUS). The amino acid change p.Ala2466Glu in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 2466 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). (less) Clinical Features: Cerebellar ataxia (present)
Likely pathogenic (Jan 31, 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: SCV004930584.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 26896183‚ 33376610‚ 32999401‚ 31429931 Comment: This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26896183, 33376610, 32999401, 31429931]. … (more) This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26896183, 33376610, 32999401, 31429931]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
Likely pathogenic (Feb 17, 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: SCV003868829.2 First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 26896183‚ 31429931‚ 32999401‚ 33376610 Comment: The p.A2466E variant (also known as c.7397C>A), located in coding exon 49 of the ATM gene, results from a C to A substitution at nucleotide … (more) The p.A2466E variant (also known as c.7397C>A), located in coding exon 49 of the ATM gene, results from a C to A substitution at nucleotide position 7397. The alanine at codon 2466 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant has been reported as homozygous and compound heterozygous with pathogenic ATM alterations in multiple patients with features of ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol, 2016 Jul;58:690-7; Shakya S et al. Clin Genet, 2019 Dec;96:566-574; Chakravorty S et al. Sci Rep, 2020 Sep;10:16184; Hettiarachchi D et al. Case Rep Genet, 2020 Dec;2020:6630300). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Likely pathogenic (Nov 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004212017.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Feb 08, 2021)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002080610.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2466 of the ATM protein (p.Ala2466Glu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 26896183, 31429931, 33376610; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 854458). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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:

The missense variant in c.7397C>A(p.Ala2466Glu) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala2466Glu variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0008% in gnomAD database. This variant has been reported to the ClinVar database as Variant of Uncertain Significance (VUS). The amino acid change p.Ala2466Glu in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 2466 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).

Comment:

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26896183, 33376610, 32999401, 31429931]. This variant is expected to disrupt protein structure [Myriad internal data].

Comment:

The p.A2466E variant (also known as c.7397C>A), located in coding exon 49 of the ATM gene, results from a C to A substitution at nucleotide position 7397. The alanine at codon 2466 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant has been reported as homozygous and compound heterozygous with pathogenic ATM alterations in multiple patients with features of ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol, 2016 Jul;58:690-7; Shakya S et al. Clin Genet, 2019 Dec;96:566-574; Chakravorty S et al. Sci Rep, 2020 Sep;10:16184; Hettiarachchi D et al. Case Rep Genet, 2020 Dec;2020:6630300). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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
Six Novel ATM Gene Variants in Sri Lankan Patients with Ataxia Telangiectasia.	Hettiarachchi D	Case reports in genetics	2020	PMID: 33376610
Expanding the genotype-phenotype correlation of childhood sensory polyneuropathy of genetic origin.	Chakravorty S	Scientific reports	2020	PMID: 32999401
Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia.	Shakya S	Clinical genetics	2019	PMID: 31429931
Longitudinal analysis of the neurological features of ataxia-telangiectasia.	Jackson TJ	Developmental medicine and child neurology	2016	PMID: 26896183

Text-mined citations for rs1324075885 ...

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.7397C>A (p.Ala2466Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1324075885 ...