NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Predisposition to cancer

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 24, 2022
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:: RCV002291559.8

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:: Predisposition to cancer
Identifiers:

Recent activity

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GSM1290448[Accession] (4)
GEO DataSets
hypothetical protein SAV14893_014890 [Streptomyces avermitilis]
hypothetical protein SAV14893_014890 [Streptomyces avermitilis]
gi|1621342902|dbj|GDY62096.1||gnl|W HX|GDY62096

Protein
PREDICTED: Mus musculus small ArfGAP 2 (Smap2), transcript variant X2, mRNA
PREDICTED: Mus musculus small ArfGAP 2 (Smap2), transcript variant X2, mRNA
gi|1720409785|ref|XM_006503379.4|

Nucleotide
stromal membrane-associated protein 2 [Mus musculus]
stromal membrane-associated protein 2 [Mus musculus]
gi|31981560|ref|NP_598477.2|

Protein
hypothetical protein SAVERM_2300 [Streptomyces avermitilis MA-4680 = NBRC 14893]
hypothetical protein SAVERM_2300 [Streptomyces avermitilis MA-4680 = NBRC 14893]
gi|29605947|dbj|BAC70011.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000891024	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Pathogenic (May 24, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000891024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Pathogenic
(May 24, 2022)

germline

clinical testing

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV000891024.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios ~2-5, PMID: 18172190, 22994785). This variant has also been reported in individuals with colon, prostate, gastric, kidney, and thyroid cancer (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic with evidence indicating lower penetrance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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