NM_007194.4(CHEK2):c.1534C>G (p.Leu512Val) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Jun 25, 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:
RCV000587712.5

Allele description [Variation Report for NM_007194.4(CHEK2):c.1534C>G (p.Leu512Val)]

NM_007194.4(CHEK2):c.1534C>G (p.Leu512Val)

Gene:
CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q12.1
Genomic location:
Preferred name:
NM_007194.4(CHEK2):c.1534C>G (p.Leu512Val)
HGVS:
  • NC_000022.11:g.28689143G>C
  • NG_008150.1:g.57692C>G
  • NG_008150.2:g.57724C>G
  • NM_001005735.2:c.1663C>G
  • NM_001257387.2:c.871C>G
  • NM_001349956.2:c.1333C>G
  • NM_007194.4:c.1534C>GMANE SELECT
  • NM_145862.2:c.1447C>G
  • NP_001005735.1:p.Leu555Val
  • NP_001244316.1:p.Leu291Val
  • NP_001336885.1:p.Leu445Val
  • NP_009125.1:p.Leu512Val
  • NP_665861.1:p.Leu483Val
  • LRG_302t1:c.1534C>G
  • LRG_302:g.57724C>G
  • LRG_302p1:p.Leu512Val
  • NC_000022.10:g.29085131G>C
  • NM_007194.3:c.1534C>G
  • O96017:p.Leu512Val
  • p.L512V
Protein change:
L291V
Links:
UniProtKB: O96017#VAR_021122; dbSNP: rs17882942
NCBI 1000 Genomes Browser:
rs17882942
Molecular consequence:
  • NM_001005735.2:c.1663C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001257387.2:c.871C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349956.2:c.1333C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007194.4:c.1534C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_145862.2:c.1447C>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
SCV000278931GeneDxcriteria provided, single submitter
Uncertain significance
(Jun 25, 2021)
germlineclinical testing

Citation Link,

SCV000698784Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(May 15, 2017)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000806874PreventionGenetics,PreventionGeneticscriteria provided, single submitter
Uncertain significance
(Dec 12, 2016)
germlineclinical testing

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

SCV001134160Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Uncertain significance
(Jul 19, 2019)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Multigene testing of moderate-risk genes: be mindful of the missense.

Young EL, Feng BJ, Stark AW, Damiola F, Durand G, Forey N, Francy TC, Gammon A, Kohlmann WK, Kaphingst KA, McKay-Chopin S, Nguyen-Dumont T, Oliver J, Paquette AM, Pertesi M, Robinot N, Rosenthal JS, Vallee M, Voegele C, Hopper JL, Southey MC, Andrulis IL, et al.

J Med Genet. 2016 Jun;53(6):366-76. doi: 10.1136/jmedgenet-2015-103398. Epub 2016 Jan 19.

PubMed [citation]
PMID:
26787654
PMCID:
PMC4893078

Linkage disequilibrium mapping of CHEK2: common variation and breast cancer risk.

Einarsdóttir K, Humphreys K, Bonnard C, Palmgren J, Iles MM, Sjölander A, Li Y, Chia KS, Liu ET, Hall P, Liu J, Wedrén S.

PLoS Med. 2006 Jun;3(6):e168. Epub 2006 May 9.

PubMed [citation]
PMID:
16671833
PMCID:
PMC1457009
See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000278931.10

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies demonstrate normal growth in response to DNA damage (Delimitsou et. al., 2019); Observed in individuals with a personal history of breast cancer (Le Calvez-Kelm 2011, Tung 2015); This variant is associated with the following publications: (PMID: 31398194, 21244692, 26787654, 27527004, 16671833, 25186627, 31106920, 30851065, 27535533)

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698784.1

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

Description

Variant summary: The CHEK2 c.1534C>G (p.Leu512Val) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution in the protein kinase domain (InterPro). 5/5 in silico tools predict benign outcome for this variant. This variant was found in 5/113850 control chromosomes including broad and large population from ExAC at a frequency of 0.0000439, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). However, it was only found in Latino subpopulation with an allele frequency of 0.000452 (5/11054 chromosomes) which is nearly 1.5 times the estimated maximal expected allele frequency, possibly suggesting that it is a rare population-specific polymorphism. However, in a case-control study, this variant was found in one breast cancer patient but not in controls (Calvez-Kelm_2011). Pathogenic variants in this gene are associated with elevated risk of breast cancer. Whether this variant is a significant risk allele needs to be further investigated. To our knowledge, the variant has not been tested by in vitro/in vivo functional assays. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is currently classified as VUS-possibly benign.

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

From PreventionGenetics,PreventionGenetics, SCV000806874.1

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134160.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 26, 2021

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