NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND CHEK2-related disorder

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 27, 2024
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV004528801.3

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:: CHEK2-related disorder
Identifiers:

Recent activity

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Homo sapiens cadherin like and PC-esterase domain containing 1 (CPED1), transcri...
Homo sapiens cadherin like and PC-esterase domain containing 1 (CPED1), transcript variant 1, mRNA
gi|1519312042|ref|NM_024913.5|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000806862	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Sep 27, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000806862

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Sep 27, 2024)

germline

clinical testing

Help

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 PreventionGenetics, part of Exact Sciences, SCV000806862.4

#	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.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs*15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128042/). Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic.

#	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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