NM_000051.4(ATM):c.1236-2A>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 10, 2022
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:: RCV000771771.7

Allele description [Variation Report for NM_000051.4(ATM):c.1236-2A>G]

NM_000051.4(ATM):c.1236-2A>G

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.1236-2A>G

HGVS:

NC_000011.10:g.108250699A>G
NG_009830.1:g.32868A>G
NM_000051.4:c.1236-2A>GMANE SELECT
NM_001351834.2:c.1236-2A>G
LRG_135t1:c.1236-2A>G
LRG_135:g.32868A>G
NC_000011.9:g.108121426A>G
NM_000051.3:c.1236-2A>G

Links:

dbSNP: rs80159221

NCBI 1000 Genomes Browser:

rs80159221

Molecular consequence:

NM_000051.4:c.1236-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001351834.2:c.1236-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000904440	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 28, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002667068	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 10, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 14695534, 15039971 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000904440

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 28, 2020)

germline

clinical testing

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

SCV002667068

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 10, 2022)

germline

clinical testing

PubMed (2)
[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

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

Nonclassical splicing mutations in the coding and noncoding regions of the ATM Gene: maximum entropy estimates of splice junction strengths.

Eng L, Coutinho G, Nahas S, Yeo G, Tanouye R, Babaei M, Dörk T, Burge C, Gatti RA.

Hum Mutat. 2004 Jan;23(1):67-76.

PubMed [citation]

PMID:: 14695534

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000904440.3

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

Description

This variant causes an A to G nucleotide substitution at the -2 position of intron 9 of the ATM gene. A RT-PCR study using cells from a carrier individual has shown that this variant activates a cryptic splice acceptor site seven nucleotides downstream of the variant position and causes the deletion of the first seven nucleotides of exon 12 (PMID: 14695534). This results in a frameshift and premature protein truncation, and lack of detectable ATM protein expression (PMID: 14695534). This variant has been observed in two unrelated individuals affected with ataxia telangiectasia (PMID: 14695534). This variant has also been observed in two related individuals affected with breast cancer (PMID: 28691344) and in two unrelated individuals affected with breast cancer with family history of breast cancer in the first degree relatives (Color internal data). 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, SCV002667068.2

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

Description

The c.1236-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the ATM gene. This alteration has been identified in the compound heterozygous state in multiple individuals with ataxia telangiectasia (A-T) (Coutinho G et al. Am J Med Genet A, 2004 Apr;126A:33-40). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Eng L et al. Hum Mutat, 2004 Jan;23:67-76; Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified 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

ClinVar

Relating variation to medicine