NM_000051.4(ATM):c.8122G>A (p.Asp2708Asn) AND not provided

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Aug 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000255899.18

Allele description [Variation Report for NM_000051.4(ATM):c.8122G>A (p.Asp2708Asn)]

NM_000051.4(ATM):c.8122G>A (p.Asp2708Asn)

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.8122G>A (p.Asp2708Asn)

HGVS:

NC_000011.10:g.108335080G>A
NG_009830.1:g.117249G>A
NG_054724.1:g.139753C>T
NM_000051.4:c.8122G>AMANE SELECT
NM_001330368.2:c.641-26009C>T
NM_001351110.2:c.*38+140C>T
NM_001351834.2:c.8122G>A
NP_000042.3:p.Asp2708Asn
NP_000042.3:p.Asp2708Asn
NP_001338763.1:p.Asp2708Asn
LRG_135t1:c.8122G>A
LRG_135:g.117249G>A
LRG_135p1:p.Asp2708Asn
NC_000011.9:g.108205807G>A
NM_000051.2:c.8122G>A
NM_000051.3:c.8122G>A
p.D2708N

Protein change:

D2708N

Links:

dbSNP: rs587782719

NCBI 1000 Genomes Browser:

rs587782719

Molecular consequence:

NM_001330368.2:c.641-26009C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+140C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.8122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.8122G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322142	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Aug 12, 2022)	germline	clinical testing	Citation Link,
SCV000883423	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Jun 24, 2018)	germline	clinical testing	Citation Link,
SCV004024725	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322142

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Aug 12, 2022)

germline

clinical testing

Citation Link,

SCV000883423

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Jun 24, 2018)

germline

clinical testing

Citation Link,

SCV004024725

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 15, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000322142.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19431188, 17124347, 22071889, 27913932, 17910737, 16941484, 23632773, 21792198, 29600275, 29909963, 27304073, 28779002, 23454770, 33436325, 29922827, 32980694, 33280026)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883423.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ATM c.8122G>A; p.Asp2708Asn variant (rs587782719), is reported in the literature in a compound heterozygous state in multiple individuals affected with ataxia-telangiectasia (A-T; Cavalieri 2006, Claes 2013, Jacquemin 2012, Magliozzi 2006, Prodosmo 2013, Reiman 2011) and one heterozygous individual with bilateral breast cancer and ovarian cancer (Tavera-Tapia 2017). This variant is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 142791), and is also largely absent from general population databases (not found in 1000 Genomes Project or Exome Variant Server, and one heterozygous individual in Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 2708 is highly conserved, and functional analyses of the variant protein show reduced kinase activity and increased radiosensitivity (Barone 2009, Claes 2013, Jacquemin 2012). Based on available information, this variant is considered to be likely pathogenic. Pathogenic variants in the ATM gene follow an autosomal recessive inheritance pattern and are associated with ataxia-telangiectasia (A-T; MIM: 208900), and an autosomal dominant inheritance pattern and are associated with an increased risk for breast cancer (MIM: 114480). References: Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-30. Cavalieri S et al. ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions. Hum Mutat. 2006 Oct;27(10):1061. Claes K et al. Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives. Neuromolecular Med. 2013 Sep;15(3):447-57. Jacquemin V et al. Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. Eur J Hum Genet. 2012 Mar;20(3):305-12. Magliozzi M et al. DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations. Dis Markers. 2006;22(4):257-64. Prodosmo A et al. p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes. J Clin Invest. 2013 Mar;123(3):1335-42. doi: 10.1172/JCI67289. Epub 2013 Feb 1. Reiman A et al. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. Br J Cancer. 2011 Aug 9;105(4):586-91. Tavera-Tapia A et al. Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene. Breast Cancer Res Treat. 2017 Feb;161(3):597-604.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004024725.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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