NM_000051.4(ATM):c.4735C>T (p.Gln1579Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 24, 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:: RCV000210197.12

Allele description [Variation Report for NM_000051.4(ATM):c.4735C>T (p.Gln1579Ter)]

NM_000051.4(ATM):c.4735C>T (p.Gln1579Ter)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.4735C>T (p.Gln1579Ter)

HGVS:

NC_000011.10:g.108293436C>T
NG_009830.1:g.75605C>T
NM_000051.4:c.4735C>TMANE SELECT
NM_001351834.2:c.4735C>T
NP_000042.3:p.Gln1579Ter
NP_000042.3:p.Gln1579Ter
NP_001338763.1:p.Gln1579Ter
LRG_135t1:c.4735C>T
LRG_135:g.75605C>T
LRG_135p1:p.Gln1579Ter
NC_000011.9:g.108164163C>T
NM_000051.3:c.4735C>T

Protein change:

Q1579*

Links:

dbSNP: rs869312755

NCBI 1000 Genomes Browser:

rs869312755

Molecular consequence:

NM_000051.4:c.4735C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.4735C>T - 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
SCV000266017	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Likely pathogenic (Nov 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000273529	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 24, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20153123, 25037873, 26845104 Citation Link,
SCV000913947	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 27, 2020)	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

SCV000266017

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Shirts et al. (Genet Med 2016))

Likely pathogenic
(Nov 20, 2015)

germline

clinical testing

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

SCV000273529

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 24, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000913947

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 27, 2020)

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	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

DNA repair alterations in children with pediatric malignancies: novel opportunities to identify patients at risk for high-grade toxicities.

Rübe CE, Fricke A, Schneider R, Simon K, Kühne M, Fleckenstein J, Gräber S, Graf N, Rübe C.

Int J Radiat Oncol Biol Phys. 2010 Oct 1;78(2):359-69. doi: 10.1016/j.ijrobp.2009.08.052. Epub 2010 Feb 12.

PubMed [citation]

PMID:: 20153123

Cognitive phenotype in ataxia-telangiectasia.

Hoche F, Frankenberg E, Rambow J, Theis M, Harding JA, Qirshi M, Seidel K, Barbosa-Sicard E, Porto L, Schmahmann JD, Kieslich M.

Pediatr Neurol. 2014 Sep;51(3):297-310. doi: 10.1016/j.pediatrneurol.2014.04.027. Epub 2014 May 5.

PubMed [citation]

PMID:: 25037873

See all PubMed Citations (4)

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000266017.1

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

From Ambry Genetics, SCV000273529.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.Q1579* pathogenic mutation (also known as c.4735C>T), located in coding exon 30 of the ATM gene, results from a C to T substitution at nucleotide position 4735. This changes the amino acid from a glutamine to a stop codon within coding exon 30. This mutation has been reported in an individual with ataxia-telangiectasia, who also carried a second ATM mutation (Hoche F et al. Pediatr. Neurol. 2014 Sep;51:297-310). It was also identified in a patient with a personal history of breast cancer and a family history of ovarian cancer (Shirts BH et al. Genet. Med. 2016 Oct;18:974-81). In addition to the clinical data presented in the literature, 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000913947.3

#	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 31 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast cancer (PMID: 26845104) and in the compound heterozygous state with a second ATM mutation in an individual affected with ataxia telangiectasia (PMID: 25037873). This variant has not been identified 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: Jun 17, 2024

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