NM_000051.4(ATM):c.2376+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 15, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000583695.6

Allele description [Variation Report for NM_000051.4(ATM):c.2376+1G>A]

NM_000051.4(ATM):c.2376+1G>A

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.2376+1G>A

HGVS:

NC_000011.10:g.108257607G>A
NG_009830.1:g.39776G>A
NM_000051.4:c.2376+1G>AMANE SELECT
NM_001351834.2:c.2376+1G>A
LRG_135t1:c.2376+1G>A
LRG_135:g.39776G>A
NC_000011.9:g.108128334G>A
NM_000051.3:c.2376+1G>A

Links:

dbSNP: rs730881347

NCBI 1000 Genomes Browser:

rs730881347

Molecular consequence:

NM_000051.4:c.2376+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001351834.2:c.2376+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000687380	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22213089, 28126470, 33471991, 35716007, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000687380

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 15, 2023)

germline

clinical testing

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

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

Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.

Verhagen MM, Last JI, Hogervorst FB, Smeets DF, Roeleveld N, Verheijen F, Catsman-Berrevoets CE, Wulffraat NM, Cobben JM, Hiel J, Brunt ER, Peeters EA, Gómez Garcia EB, van der Knaap MS, Lincke CR, Laan LA, Tijssen MA, van Rijn MA, Majoor-Krakauer D, Visser M, van 't Veer LJ, Kleijer WJ, et al.

Hum Mutat. 2012 Mar;33(3):561-71. doi: 10.1002/humu.22016. Epub 2012 Jan 25.

PubMed [citation]

PMID:: 22213089

Ataxia-telangiectasia: Immunodeficiency and survival.

van Os NJH, Jansen AFM, van Deuren M, Haraldsson A, van Driel NTM, Etzioni A, van der Flier M, Haaxma CA, Morio T, Rawat A, Schoenaker MHD, Soresina A, Taylor AMR, van de Warrenburg BPC, Weemaes CMR, Roeleveld N, Willemsen MAAP.

Clin Immunol. 2017 May;178:45-55. doi: 10.1016/j.clim.2017.01.009. Epub 2017 Jan 24.

PubMed [citation]

PMID:: 28126470

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000687380.5

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

Description

This variant causes a G to A nucleotide substitution at the +1 position of intron 15 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have shown this variant disrupts splicing and results in in-frame skipping of exon 15 (PMID: 35716007). This variant has been reported in the compound heterozygous state in an individual affected with ataxia-telangiectasia (PMID: 22213089, 28126470). In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 unaffected controls (PMID: 33471991). 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 Likely 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: Feb 20, 2024

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