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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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000217201Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Aug 4, 2023)
germlineclinical testing

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

Citation Link,

SCV001735827Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Dec 13, 2022)
germlineclinical testing

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

SCV002530636Sema4, Sema4
criteria provided, single submitter

(Sema4 Curation Guidelines)
Pathogenic
(Nov 24, 2021)
germlinecuration

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Sema4, Sema4, SCV002530636.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024