NM_000051.4(ATM):c.8152-1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 24, 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:: RCV000574836.15

Allele description [Variation Report for NM_000051.4(ATM):c.8152-1G>A]

NM_000051.4(ATM):c.8152-1G>A

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.8152-1G>A

HGVS:

NC_000011.10:g.108335844G>A
NG_009830.1:g.118013G>A
NG_054724.1:g.138989C>T
NM_000051.4:c.8152-1G>AMANE SELECT
NM_001330368.2:c.641-26773C>T
NM_001351110.2:c.695-552C>T
NM_001351834.2:c.8152-1G>A
LRG_135t1:c.8152-1G>A
LRG_135:g.118013G>A
NC_000011.9:g.108206571G>A
NM_000051.3:c.8152-1G>A

Links:

dbSNP: rs1398616877

NCBI 1000 Genomes Browser:

rs1398616877

Molecular consequence:

NM_001330368.2:c.641-26773C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.695-552C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.8152-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001351834.2:c.8152-1G>A - 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
SCV000660743	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Aug 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28975465, 31130284 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000660743

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Aug 24, 2023)

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

Expanding the spectrum of germline variants in cancer.

Siraj AK, Masoodi T, Bu R, Parvathareddy SK, Al-Badawi IA, Al-Sanea N, Ashari LH, Abduljabbar A, Alhomoud S, Al-Sobhi SS, Tulbah A, Ajarim D, Alzoman K, Aljuboury M, Yousef HB, Al-Dawish M, Al-Dayel F, Alkuraya FS, Al-Kuraya KS.

Hum Genet. 2017 Nov;136(11-12):1431-1444. doi: 10.1007/s00439-017-1845-0. Epub 2017 Oct 3.

PubMed [citation]

PMID:: 28975465

Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.

Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N, Alowain M, Alzaidan H, Alsayed M, Subhani S, Cupler E, Faden M, Alhashem A, Qari A, Chedrawi A, Aldhalaan H, Kurdi W, Khan S, Rahbeeni Z, Alotaibi M, Goljan E, Elbardisy H, et al.

Am J Hum Genet. 2019 Jun 6;104(6):1182-1201. doi: 10.1016/j.ajhg.2019.04.011. Epub 2019 May 23. Erratum in: Am J Hum Genet. 2019 Oct 3;105(4):879. doi: 10.1016/j.ajhg.2019.09.019.

PubMed [citation]

PMID:: 31130284
PMCID:: PMC6562004

Details of each submission

From Ambry Genetics, SCV000660743.7

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

Description

The c.8152-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 55 of the ATM gene. This alteration has been observed in an individual with breast cancer (Siraj AK et al. Hum Genet, 2017 11;136:1431-1444). This variant has been reported in a homozygous state in an individual with dystonia, microcephaly, speech delay, fine and gross motor delay, but without ataxia and telangiectasia (Monies D et al. Am J Hum Genet, 2019 Jun;104:1182-1201). 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 (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 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: Oct 26, 2024

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