NM_000051.4(ATM):c.7928-2A>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 1, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000581443.16

Allele description [Variation Report for NM_000051.4(ATM):c.7928-2A>G]

NM_000051.4(ATM):c.7928-2A>G

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.7928-2A>G

HGVS:

NC_000011.10:g.108333884A>G
NG_009830.1:g.116053A>G
NG_054724.1:g.140949T>C
NM_000051.4:c.7928-2A>GMANE SELECT
NM_001330368.2:c.641-24813T>C
NM_001351110.2:c.*38+1336T>C
NM_001351834.2:c.7928-2A>G
LRG_135t1:c.7928-2A>G
LRG_135:g.116053A>G
NC_000011.9:g.108204611A>G
NM_000051.3:c.7928-2A>G

Links:

dbSNP: rs864622610

NCBI 1000 Genomes Browser:

rs864622610

Molecular consequence:

NM_001330368.2:c.641-24813T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+1336T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7928-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001351834.2:c.7928-2A>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000687805	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 4, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19781682, 30287823, 25741868
SCV002676552	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 1, 2023)	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

SCV000687805

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 4, 2021)

germline

clinical testing

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

SCV002676552

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 1, 2023)

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

Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.

Tavtigian SV, Oefner PJ, Babikyan D, Hartmann A, Healey S, Le Calvez-Kelm F, Lesueur F, Byrnes GB, Chuang SC, Forey N, Feuchtinger C, Gioia L, Hall J, Hashibe M, Herte B, McKay-Chopin S, Thomas A, Vallée MP, Voegele C, Webb PM, Whiteman DC; Australian Cancer Study.; et al.

Am J Hum Genet. 2009 Oct;85(4):427-46. doi: 10.1016/j.ajhg.2009.08.018. Epub 2009 Sep 24.

PubMed [citation]

PMID:: 19781682
PMCID:: PMC2756555

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 (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000687805.3

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

Description

This variant causes an A to G nucleotide substitution at the -2 position of intron 53 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature and has been reported in control individuals (PMID: 19781682, 30287823). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site, c.7928-2A>T and c.7928-1G>A, are known to be disease-causing (ClinVar variation ID: 220626, 482651). 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

From Ambry Genetics, SCV002676552.3

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

Description

The c.7928-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 53 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was not observed in 7051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing; however, this alteration leads to the use of an in frame alternate splice acceptor site (Ambry internal data). The clinical relevance of this splicing event is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: Nov 10, 2024

ClinVar

Relating variation to medicine