NM_000051.4(ATM):c.1120C>T (p.Gln374Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 3, 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:: RCV001185328.7

Allele description [Variation Report for NM_000051.4(ATM):c.1120C>T (p.Gln374Ter)]

NM_000051.4(ATM):c.1120C>T (p.Gln374Ter)

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.1120C>T (p.Gln374Ter)

HGVS:

NC_000011.10:g.108248987C>T
NG_009830.1:g.31156C>T
NM_000051.4:c.1120C>TMANE SELECT
NM_001351834.2:c.1120C>T
NP_000042.3:p.Gln374Ter
NP_000042.3:p.Gln374Ter
NP_001338763.1:p.Gln374Ter
LRG_135t1:c.1120C>T
LRG_135:g.31156C>T
LRG_135p1:p.Gln374Ter
NC_000011.9:g.108119714C>T
NM_000051.3:c.1120C>T

Protein change:

Q374*

Links:

dbSNP: rs1185204988

NCBI 1000 Genomes Browser:

rs1185204988

Molecular consequence:

NM_000051.4:c.1120C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.1120C>T - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

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Homo sapiens chromosome 21 open reading frame 66 (C21orf66), transcript variant ...
Homo sapiens chromosome 21 open reading frame 66 (C21orf66), transcript variant 4, mRNA
gi|22035563|ref|NM_058191.2|

Nucleotide
Zea mays uncharacterized LOC100274182 (LOC100274182), mRNA
Zea mays uncharacterized LOC100274182 (LOC100274182), mRNA
gi|226505463|ref|NM_001148556.1|

Nucleotide
Tfp1p [Saccharomyces cerevisiae JAY291]
Tfp1p [Saccharomyces cerevisiae JAY291]
gi|256270281|gb|EEU05498.1||gnl|WGS |C1Q_04144

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001351523	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9682216, 10425038, 25741868
SCV002746004	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 22, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12815592, 17968022, 21933854, 25525159, 9682216 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001351523

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 3, 2023)

germline

clinical testing

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

SCV002746004

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 22, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy.

Castellví-Bel S, Sheikhavandi S, Telatar M, Tai LQ, Hwang M, Wang Z, Yang Z, Cheng R, Gatti RA.

Hum Mutat. 1999;14(2):156-62.

PubMed [citation]

PMID:: 10425038

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

See all PubMed Citations (7)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001351523.3

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

Description

This variant changes 1 nucleotide in exon 9 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, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia cancer in the literature and is considered a founder in the Costa Rican population (PMID 9682216, 10425038). 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. 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

From Ambry Genetics, SCV002746004.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Q374* pathogenic mutation (also known as c.1120C>T), located in coding exon 8 of the ATM gene, results from a C to T substitution at nucleotide position 1120. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been described as a Costa Rican founder mutation that has been observed in multiple ataxia-telangiectasia patients (Telatar M et al. Mol. Genet. Metab., 1998 May;64:36-43). This mutation has also been reported in conjunction with deletion of chromosome 11q in patients with chronic lymphocytic leukemia (Austen B et al. J. Clin. Oncol., 2007 Dec;25:5448-57; Skowronska A et al. Haematologica, 2012 Jan;97:142-6). 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

Last Updated: Sep 29, 2024

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