VCV000231789.16 - ClinVar

NM_000051.4(ATM):c.7408T>G (p.Tyr2470Asp)

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.

Pathogenic/Likely pathogenic

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.7408T>G (p.Tyr2470Asp)

Variation ID: 231789 Accession: VCV000231789.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108330314 (GRCh38) [ NCBI UCSC ] 11: 108201041 (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	May 29, 2016	May 1, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.7408T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Tyr2470Asp	missense
NM_001330368.2:c.641-21243A>C		intron variant
NM_001351110.2:c.*38+4906A>C		intron variant
NM_001351834.2:c.7408T>G	NP_001338763.1:p.Tyr2470Asp	missense
NC_000011.10:g.108330314T>G
NC_000011.9:g.108201041T>G
NG_009830.1:g.112483T>G
NG_054724.1:g.144519A>C
LRG_135:g.112483T>G
LRG_135t1:c.7408T>G	LRG_135p1:p.Tyr2470Asp
	Q13315:p.Tyr2470Asp

... more HGVS ... less HGVS

Protein change

Y2470D

Other names

Canonical SPDI

NC_000011.10:108330313:T: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.

Links

ClinGen: CA10579258 UniProtKB: Q13315#VAR_010858 dbSNP: rs876659365 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	Likely pathogenic (1)	criteria provided, single submitter	Mar 28, 2023	RCV000220077.12
Familial cancer of breast	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV002247654.11
Ataxia-telangiectasia syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 3, 2023	RCV000528764.17

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.
Likely pathogenic (Dec 21, 2016)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000788870.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018	Publications: PubMed (3) PubMed: 19691550‚ 9887333‚ 21665257
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518540.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Feb 03, 2023)	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: SCV000622744.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 9887333‚ 19691550‚ 21665257 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, … (more) For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 231789). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 9887333, 19691550, 21665257). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2470 of the ATM protein (p.Tyr2470Asp). (less)
Likely pathogenic (Mar 28, 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: SCV000275741.8 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 19691550‚ 21665257‚ 22927201‚ 23454770‚ 30613976‚ 9887333 Comment: The p.Y2470D variant (also known as c.7408T>G), located in coding exon 49 of the ATM gene, results from a T to G substitution at nucleotide … (more) The p.Y2470D variant (also known as c.7408T>G), located in coding exon 49 of the ATM gene, results from a T to G substitution at nucleotide position 7408. The tyrosine at codon 2470 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration has been reported in multiple patients with ataxia telangiectasia (A-T) including one patient who was homozygous for this variant (Sandoval N, Hum. Mol. Genet. 1999 Jan; Chessa L, Ann. Hum. Genet. 2009 Sep; 73(Pt 5):532-9; 8(1):69-79; Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1; Zannolli R et al. Mov Disord, 2012 Sep;27:1312-6; Prodosmo A, J. Clin. Invest. 2013 Mar; 123(3):1335-42). This alteration was also detected in a cohort of 523 Italian male breast cancer patients screened by a multigene custom panel of 50 cancer-associated genes (Rizzolo P et al. Int J Cancer, 2019 07;145:390-400). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)
Pathogenic (Jun 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210222.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
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: SCV004932212.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 9887333‚ 19691550‚ 21665257 Comment: This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9887333, 19691550, 21665257].

Comment:

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 231789). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 9887333, 19691550, 21665257). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2470 of the ATM protein (p.Tyr2470Asp).

Comment:

The p.Y2470D variant (also known as c.7408T>G), located in coding exon 49 of the ATM gene, results from a T to G substitution at nucleotide position 7408. The tyrosine at codon 2470 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration has been reported in multiple patients with ataxia telangiectasia (A-T) including one patient who was homozygous for this variant (Sandoval N, Hum. Mol. Genet. 1999 Jan; Chessa L, Ann. Hum. Genet. 2009 Sep; 73(Pt 5):532-9; 8(1):69-79; Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1; Zannolli R et al. Mov Disord, 2012 Sep;27:1312-6; Prodosmo A, J. Clin. Invest. 2013 Mar; 123(3):1335-42). This alteration was also detected in a cohort of 523 Italian male breast cancer patients screened by a multigene custom panel of 50 cancer-associated genes (Rizzolo P et al. Int J Cancer, 2019 07;145:390-400). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.	Rizzolo P	International journal of cancer	2019	PMID: 30613976
p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes.	Prodosmo A	The Journal of clinical investigation	2013	PMID: 23454770
A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia.	Zannolli R	Movement disorders : official journal of the Movement Disorder Society	2012	PMID: 22927201
Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.	Micol R	The Journal of allergy and clinical immunology	2011	PMID: 21665257
Founder effects for ATM gene mutations in Italian Ataxia Telangiectasia families.	Chessa L	Annals of human genetics	2009	PMID: 19691550
Characterization of ATM gene mutations in 66 ataxia telangiectasia families.	Sandoval N	Human molecular genetics	1999	PMID: 9887333

Text-mined citations for rs876659365 ...

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 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.7408T>G (p.Tyr2470Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs876659365 ...