NM_000051.4(ATM):c.4735C>T (p.Gln1579Ter) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 27, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000210197.6

Allele description [Variation Report for NM_000051.4(ATM):c.4735C>T (p.Gln1579Ter)]

NM_000051.4(ATM):c.4735C>T (p.Gln1579Ter)

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.4735C>T (p.Gln1579Ter)
HGVS:
  • NC_000011.10:g.108293436C>T
  • NG_009830.1:g.75605C>T
  • NM_000051.3:c.4735C>T
  • NM_000051.4:c.4735C>TMANE SELECT
  • NM_001351834.2:c.4735C>T
  • NP_000042.3:p.Gln1579Ter
  • NP_000042.3:p.Gln1579Ter
  • NP_001338763.1:p.Gln1579Ter
  • LRG_135t1:c.4735C>T
  • LRG_135:g.75605C>T
  • LRG_135p1:p.Gln1579Ter
  • NC_000011.9:g.108164163C>T
Protein change:
Q1579*
Links:
dbSNP: rs869312755
NCBI 1000 Genomes Browser:
rs869312755
Molecular consequence:
  • NM_000051.3:c.4735C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000051.4:c.4735C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001351834.2:c.4735C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
2

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000266017University of Washington Department of Laboratory Medicine, University of Washingtoncriteria provided, single submitter
Likely pathogenic
(Nov 20, 2015)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000273529Ambry Geneticscriteria provided, single submitter
Pathogenic
(Oct 17, 2017)
germlineclinical testing

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

Citation Link,

SCV000913947Color Health, Inccriteria provided, single submitter
Pathogenic
(Oct 27, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

DNA repair alterations in children with pediatric malignancies: novel opportunities to identify patients at risk for high-grade toxicities.

Rübe CE, Fricke A, Schneider R, Simon K, Kühne M, Fleckenstein J, Gräber S, Graf N, Rübe C.

Int J Radiat Oncol Biol Phys. 2010 Oct 1;78(2):359-69. doi: 10.1016/j.ijrobp.2009.08.052. Epub 2010 Feb 12.

PubMed [citation]
PMID:
20153123

Cognitive phenotype in ataxia-telangiectasia.

Hoche F, Frankenberg E, Rambow J, Theis M, Harding JA, Qirshi M, Seidel K, Barbosa-Sicard E, Porto L, Schmahmann JD, Kieslich M.

Pediatr Neurol. 2014 Sep;51(3):297-310. doi: 10.1016/j.pediatrneurol.2014.04.027. Epub 2014 May 5.

PubMed [citation]
PMID:
25037873
See all PubMed Citations (4)

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000266017.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Ambry Genetics, SCV000273529.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The p.Q1579* pathogenic mutation (also known as c.4735C>T), located in coding exon 30 of the ATM gene, results from a C to T substitution at nucleotide position 4735. This changes the amino acid from a glutamine to a stop codon within coding exon 30. This mutation has been reported in an individual with ataxia-telangiectasia, who also carried a second ATM mutation (Hoche F et al. Pediatr. Neurol. 2014 Sep;51:297-310). It was also identified in a patient with a personal history of breast cancer and a family history of ovarian cancer (Shirts BH et al. Genet. Med. 2016 Oct;18:974-81). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000913947.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant changes 1 nucleotide in exon 31 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast cancer (PMID: 26845104) and in the compound heterozygous state with a second ATM mutation in an individual affected with ataxia telangiectasia (PMID: 25037873). 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 Pathogenic.

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

Last Updated: Oct 30, 2021

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