NM_000051.4(ATM):c.2135C>A (p.Ser712Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 1, 2024
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:: RCV003584121.2

Allele description [Variation Report for NM_000051.4(ATM):c.2135C>A (p.Ser712Ter)]

NM_000051.4(ATM):c.2135C>A (p.Ser712Ter)

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.2135C>A (p.Ser712Ter)

HGVS:

NC_000011.10:g.108256225C>A
NG_009830.1:g.38394C>A
NM_000051.4:c.2135C>AMANE SELECT
NM_001351834.2:c.2135C>A
NP_000042.3:p.Ser712Ter
NP_000042.3:p.Ser712Ter
NP_001338763.1:p.Ser712Ter
LRG_135t1:c.2135C>A
LRG_135:g.38394C>A
LRG_135p1:p.Ser712Ter
NC_000011.9:g.108126952C>A
NM_000051.3:c.2135C>A
NM_000051.3:c.2135C>A

Protein change:

S712*

Molecular consequence:

NM_000051.4:c.2135C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.2135C>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004357212	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 31, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21665257, 25741868
SCV005167850	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004357212

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 31, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005167850

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 1, 2024)

germline

clinical testing

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

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

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

Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.

Micol R, Ben Slama L, Suarez F, Le Mignot L, Beauté J, Mahlaoui N, Dubois d'Enghien C, Laugé A, Hall J, Couturier J, Vallée L, Delobel B, Rivier F, Nguyen K, Billette de Villemeur T, Stephan JL, Bordigoni P, Bertrand Y, Aladjidi N, Pedespan JM, Thomas C, Pellier I, et al.

J Allergy Clin Immunol. 2011 Aug;128(2):382-9.e1. doi: 10.1016/j.jaci.2011.03.052. Epub 2011 Jun 12.

PubMed [citation]

PMID:: 21665257

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004357212.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant changes 1 nucleotide in exon 14 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 ataxia-telangiectasia who also carried another pathogenic variant in ATM (PMID: 21665257). 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

From Ambry Genetics, SCV005167850.1

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

Description

The p.S712* pathogenic mutation (also known as c.2135C>A), located in coding exon 13 of the ATM gene, results from a C to A substitution at nucleotide position 2135. This changes the amino acid from a serine to a stop codon within coding exon 13. This alteration has been reported, in conjunction with a second truncating ATM variant, in a patient with ataxia-telangiectasia (Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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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