NM_000051.4(ATM):c.3806A>G (p.Lys1269Arg) AND not provided

Clinical significance:Uncertain significance (Last evaluated: May 5, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000590439.5

Allele description [Variation Report for NM_000051.4(ATM):c.3806A>G (p.Lys1269Arg)]

NM_000051.4(ATM):c.3806A>G (p.Lys1269Arg)

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.3806A>G (p.Lys1269Arg)
HGVS:
  • NC_000011.10:g.108284286A>G
  • NG_009830.1:g.66455A>G
  • NM_000051.3:c.3806A>G
  • NM_000051.4:c.3806A>GMANE SELECT
  • NM_001351834.2:c.3806A>G
  • NP_000042.3:p.Lys1269Arg
  • NP_000042.3:p.Lys1269Arg
  • NP_001338763.1:p.Lys1269Arg
  • LRG_135t1:c.3806A>G
  • LRG_135:g.66455A>G
  • LRG_135p1:p.Lys1269Arg
  • NC_000011.9:g.108155013A>G
  • p.K1269R
Protein change:
K1269R
Links:
dbSNP: rs146017595
NCBI 1000 Genomes Browser:
rs146017595
Molecular consequence:
  • NM_000051.3:c.3806A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000051.4:c.3806A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.3806A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000564632GeneDxcriteria provided, single submitter
Uncertain significance
(May 5, 2021)
germlineclinical testing

Citation Link,

SCV000694266Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Jun 20, 2016)
germlineclinical testing

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001742600Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensusno assertion criteria providedUncertain significancegermlineclinical testing

SCV001954570Human Genetics - Radboudumc,Radboudumc - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedUncertain significancegermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000564632.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Observed in individuals with personal or family history of breast cancer (Decker 2017, Dominguez-Valentin 2019); Published functional studies suggest this variant may impact splicing resulting in several aberrant transcripts, but the effect was not complete as some full length transcript was also present in a mini gene assay (Dominguez-Valentin 2019); In silico analysis supports a deleterious effect on splicing; Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 31811167)

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694266.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: The ATM c.3806A>G (p.Lys1269Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 3/120788 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. It has been reported by two labs in ClinVar without evidence to independently evaluate and they have classified it as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.

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

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001742600.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Human Genetics - Radboudumc,Radboudumc - VKGL Data-share Consensus, SCV001954570.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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