NM_000051.4(ATM):c.802C>T (p.Gln268Ter) AND Ataxia-telangiectasia syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 11, 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:
RCV000169336.5

Allele description [Variation Report for NM_000051.4(ATM):c.802C>T (p.Gln268Ter)]

NM_000051.4(ATM):c.802C>T (p.Gln268Ter)

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.802C>T (p.Gln268Ter)
HGVS:
  • NC_000011.10:g.108244927C>T
  • NG_009830.1:g.27096C>T
  • NM_000051.3:c.802C>T
  • NM_000051.4:c.802C>TMANE SELECT
  • NM_001351834.2:c.802C>T
  • NP_000042.3:p.Gln268Ter
  • NP_000042.3:p.Gln268Ter
  • NP_001338763.1:p.Gln268Ter
  • LRG_135t1:c.802C>T
  • LRG_135:g.27096C>T
  • LRG_135p1:p.Gln268Ter
  • NC_000011.9:g.108115654C>T
Protein change:
Q268*
Links:
dbSNP: rs557012154
NCBI 1000 Genomes Browser:
rs557012154
Molecular consequence:
  • NM_000051.3:c.802C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000051.4:c.802C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001351834.2:c.802C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Ataxia-telangiectasia syndrome (AT)
Synonyms:
Louis-Bar syndrome; Cerebello-oculocutaneous telangiectasia; Immunodeficiency with ataxia telangiectasia; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008840; MedGen: C0004135; Orphanet: 100; OMIM: 208900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000220682Counsylcriteria provided, single submitter
Likely pathogenic
(Sep 10, 2014)
unknownliterature only

PubMed (5)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000694369Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Sep 26, 2016)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000749006Invitaecriteria provided, single submitter
Pathogenic
(Sep 11, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Fragments of ATM which have dominant-negative or complementing activity.

Morgan SE, Lovly C, Pandita TK, Shiloh Y, Kastan MB.

Mol Cell Biol. 1997 Apr;17(4):2020-9.

PubMed [citation]
PMID:
9121450
PMCID:
PMC232049

ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.

Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D; Breast Cancer Susceptibility Collaboration (UK)., Easton DF, Stratton MR, Rahman N.

Nat Genet. 2006 Aug;38(8):873-5. Epub 2006 Jul 9.

PubMed [citation]
PMID:
16832357
See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000220682.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694369.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: The ATM c.802C>T (p.Gln268X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, this variant will be expected to truncate the catalytic and FAT domains and armadillo-type fold (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp393X, p.Gln1017X etc.). This variant was found in 2/125724 control chromosomes at a frequency of 0.0000159, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). In literature, this variant has been reported in two patients with Ataxia-Telangiectasia in compound heterozygous with another variant (Teraoka_1999, Buzin_2003). Functional analysis using nested-PCR cDNAs of a cell line containing this variant showed missplicing of exon 9 (Teraoka_1999). The effect was the partial skipping of the exon. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Likely Pathogenic.

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

From Invitae, SCV000749006.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Gln268*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs557012154, ExAC 0.002%). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 10330348, 12552559). ClinVar contains an entry for this variant (Variation ID: 188961). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been 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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