NM_000051.4(ATM):c.7032G>A (p.Trp2344Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 28, 2021
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:: RCV000493110.12

Allele description [Variation Report for NM_000051.4(ATM):c.7032G>A (p.Trp2344Ter)]

NM_000051.4(ATM):c.7032G>A (p.Trp2344Ter)

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.7032G>A (p.Trp2344Ter)

HGVS:

NC_000011.10:g.108327701G>A
NG_009830.1:g.109870G>A
NG_054724.1:g.147132C>T
NM_000051.4:c.7032G>AMANE SELECT
NM_001330368.2:c.641-18630C>T
NM_001351110.2:c.*38+7519C>T
NM_001351834.2:c.7032G>A
NP_000042.3:p.Trp2344Ter
NP_000042.3:p.Trp2344Ter
NP_001338763.1:p.Trp2344Ter
LRG_135t1:c.7032G>A
LRG_135:g.109870G>A
LRG_135p1:p.Trp2344Ter
NC_000011.9:g.108198428G>A
NM_000051.3:c.7032G>A

Protein change:

W2344*

Links:

dbSNP: rs1131691162

NCBI 1000 Genomes Browser:

rs1131691162

Molecular consequence:

NM_001330368.2:c.641-18630C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+7519C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7032G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.7032G>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000581464	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Dec 28, 2021)	germline	clinical testing	Citation Link,
SCV002536920	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Apr 29, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004361825	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 30, 2021)	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

SCV000581464

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Dec 28, 2021)

germline

clinical testing

Citation Link,

SCV002536920

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Apr 29, 2021)

germline

curation

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

Citation Link,

SCV004361825

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 30, 2021)

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	unknown	1	not provided	not provided	1	not provided	clinical testing, curation

Citations

PubMed

Functional classification of ATM variants in ataxia-telangiectasia patients.

Fiévet A, Bellanger D, Rieunier G, Dubois d'Enghien C, Sophie J, Calvas P, Carriere JP, Anheim M, Castrioto A, Flabeau O, Degos B, Ewenczyk C, Mahlaoui N, Touzot F, Suarez F, Hully M, Roubertie A, Aladjidi N, Tison F, Antoine-Poirel H, Dahan K, Doummar D, et al.

Hum Mutat. 2019 Oct;40(10):1713-1730. doi: 10.1002/humu.23778. Epub 2019 May 17.

PubMed [citation]

PMID:: 31050087

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 Ambry Genetics, SCV000581464.5

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

Description

The p.W2344* pathogenic mutation (also known as c.7032G>A), located in coding exon 47 of the ATM gene, results from a G to A substitution at nucleotide position 7032. This changes the amino acid from a tryptophan to a stop codon within coding exon 47. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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

From Sema4, Sema4, SCV002536920.1

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

From Color Diagnostics, LLC DBA Color Health, SCV004361825.1

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

Description

This variant changes 1 nucleotide in exon 48 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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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