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NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Li-Fraumeni syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 25, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000587467.10

Allele description [Variation Report for NM_007194.4(CHEK2):c.1100del (p.Thr367fs)]

NM_007194.4(CHEK2):c.1100del (p.Thr367fs)

Gene:
CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
22q12.1
Genomic location:
Preferred name:
NM_007194.4(CHEK2):c.1100del (p.Thr367fs)
Other names:
NP_009125.1:p.Thr367MetfsTer15
HGVS:
  • NC_000022.11:g.28695869del
  • NG_008150.2:g.50998del
  • NM_001005735.2:c.1229del
  • NM_001257387.2:c.437del
  • NM_001349956.2:c.899del
  • NM_007194.4:c.1100delMANE SELECT
  • NM_145862.2:c.1013del
  • NP_001005735.1:p.Thr410fs
  • NP_001244316.1:p.Thr146fs
  • NP_001336885.1:p.Thr300fs
  • NP_009125.1:p.Thr367fs
  • NP_665861.1:p.Thr338fs
  • LRG_302t1:c.1100del
  • LRG_302:g.50998del
  • LRG_302p1:p.Thr367fs
  • NC_000022.10:g.29091857del
  • NC_000022.10:g.29091857delG
  • NG_008150.1:g.50966del
  • NM_001005735.1:c.1229del
  • NM_001005735.1:c.1229delC
  • NM_001005735.2:c.1229delC
  • NM_007194.3:c.1100delC
  • NM_007194.4:c.1100delCMANE SELECT
  • c.1100delC
  • p.T367MFS*15
  • p.T367MfsX15
  • p.Thr367Metfs*15
  • p.Thr367MetfsX15
  • p.Thr367fs
  • p.Thr410fs
Protein change:
T146fs
Links:
OMIM: 604373.0001; dbSNP: rs555607708
NCBI 1000 Genomes Browser:
rs555607708
Molecular consequence:
  • NM_001005735.2:c.1229del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001257387.2:c.437del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001349956.2:c.899del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007194.4:c.1100del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_145862.2:c.1013del - frameshift variant - [Sequence Ontology: SO:0001589]
Functional consequence:
Uncertain function

Condition(s)

Name:
Li-Fraumeni syndrome (LFS)
Synonyms:
Sarcoma family syndrome of Li and Fraumeni
Identifiers:
MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000698761Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jul 25, 2019) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

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

Citations

PubMed

Response to DNA damage of CHEK2 missense mutations in familial breast cancer.

Roeb W, Higgins J, King MC.

Hum Mol Genet. 2012 Jun 15;21(12):2738-44. doi: 10.1093/hmg/dds101. Epub 2012 Mar 13.

PubMed [citation]
PMID:
22419737
PMCID:
PMC3363333

Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.

Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA.

Science. 1999 Dec 24;286(5449):2528-31.

PubMed [citation]
PMID:
10617473
See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698761.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Nov 3, 2024