NM_000051.4(ATM):c.901+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 4, 2023
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:: RCV000166407.13

Allele description [Variation Report for NM_000051.4(ATM):c.901+1G>A]

NM_000051.4(ATM):c.901+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.901+1G>A

HGVS:

NC_000011.10:g.108245027G>A
NG_009830.1:g.27196G>A
NM_000051.4:c.901+1G>AMANE SELECT
NM_001351834.2:c.901+1G>A
LRG_135t1:c.901+1G>A
LRG_135:g.27196G>A
NC_000011.9:g.108115754G>A
NM_000051.3:c.901+1G>A

Links:

dbSNP: rs748840480

NCBI 1000 Genomes Browser:

rs748840480

Molecular consequence:

NM_000051.4:c.901+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001351834.2:c.901+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
SCV000217201	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 4, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12815592, 18321536, 28008555, 28281021 Citation Link,
SCV001735827	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12815592, 18321536, 28008555, 25741868
SCV002530636	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Nov 24, 2021)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 12815592, 21665257, 29625052, 31206626, 28281021, 31050087 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000217201

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 4, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001735827

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 13, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002530636

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Nov 24, 2021)

germline

curation

PubMed (6)
[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, curation

Citations

PubMed

Rapid screen for truncating ATM mutations by PTT-ELISA.

Du L, Lai CH, Concannon P, Gatti RA.

Mutat Res. 2008 Apr 2;640(1-2):139-44. doi: 10.1016/j.mrfmmm.2008.01.002. Epub 2008 Jan 31.

PubMed [citation]

PMID:: 18321536

Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results.

Pritzlaff M, Summerour P, McFarland R, Li S, Reineke P, Dolinsky JS, Goldgar DE, Shimelis H, Couch FJ, Chao EC, LaDuca H.

Breast Cancer Res Treat. 2017 Feb;161(3):575-586. doi: 10.1007/s10549-016-4085-4. Epub 2016 Dec 22.

PubMed [citation]

PMID:: 28008555
PMCID:: PMC5241330

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000217201.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.901+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the ATM gene. This alteration was identified in conjunction with a truncating ATM mutation in an individual diagnosed with ataxia-telangiectasia (Mitui M et al. Hum. Mutat. 2003 Jul;22(1):43-50). This alteration was also reported in a male diagnosed with breast cancer and an individual diagnosed with ovarian cancer (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586; Crawford B et al. Breast Cancer Res. Treat. 2017 Jun;163(2):383-390). This alteration is also known as IVS9+1G>A in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice donor 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 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

From Color Diagnostics, LLC DBA Color Health, SCV001735827.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant causes a G to A nucleotide substitution at the +1 position of intron 7 of the ATM gene. This variant is also known as IVS9+1G>A in the literature. Functional studies using patient-derived lymphoblastoid cells showed skipping of exon 7 and premature protein termination (PMID: 18321536). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 12815592, 18321536). This variant also has been reported in an individual affected with male breast cancer (PMID: 28008555). This variant has been identified in 5/276176 chromosomes 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 Sema4, Sema4, SCV002530636.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

#	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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