NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Breast and colorectal cancer, susceptibility to

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 20, 2015
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000210137.14

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

Observations:

Condition(s)

Name:: Breast and colorectal cancer, susceptibility to
Synonyms:: HBCC, susceptibility to
Identifiers:: MedGen: CN068920

Recent activity

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glutamyl-tRNA(Gln) amidotransferase subunit D (gatD) [uncultured marine thaumarc...
glutamyl-tRNA(Gln) amidotransferase subunit D (gatD) [uncultured marine thaumarchaeote KM3_74_C10]
gi|663526297|gb|AIF16475.1|

Protein
Bacillus pumilus strain KMS50 16S ribosomal RNA gene, partial sequence
Bacillus pumilus strain KMS50 16S ribosomal RNA gene, partial sequence
gi|1102130577|gb|KY119370.1|

Nucleotide
PAW domain-containing protein [Caenorhabditis elegans]
PAW domain-containing protein [Caenorhabditis elegans]
gi|922581394|ref|NP_001300267.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000266067	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Pathogenic (Nov 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004046245	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000266067

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Shirts et al. (Genet Med 2016))

Pathogenic
(Nov 20, 2015)

germline

clinical testing

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

SCV004046245

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	2	not provided	not provided	2	not provided	clinical testing
not provided	germline	yes	5	not provided	not provided	5	not provided	clinical testing

Citations

PubMed

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.

Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.

PubMed [citation]

PMID:: 26845104

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000266067.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)
2	not provided	1	not provided	not provided	clinical testing	PubMed (1)
3	not provided	1	not provided	not provided	clinical testing	PubMed (1)
4	not provided	1	not provided	not provided	clinical testing	PubMed (1)
5	not provided	1	not provided	not provided	clinical testing	PubMed (1)
6	not provided	1	not provided	not provided	clinical testing	PubMed (1)
7	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	germline	no	1	not provided	not provided		1	not provided	not provided	not provided
6	germline	no	1	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046245.1

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

Description

This variant is also referred to as c.1100delC (p.Thr367MetfsTer15) (NM_007194.3) in the literature. This deletion in exon 12 of 16 causes a frameshift and a premature stop codon at residue 424 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). The c.1229del (p.Thr410MetfsTer15) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.2% (585/275092) and is present in the homozygous state at a frequency of 0.0004% (1/275092). This variant is enriched in the European (Finnish) population (MAF=0.87%). Based on two large case-control studies, the relative risk for female breast cancer associated with the c.1229del variant was 3.0 (90% CI, 2.6-3.5) (PMID: 26014596, 15122511, 23109706). Additionally, a meta-analysis reported a relative risk of 1.88 (95% C.I. 1.29-2.73) for colorectal cancer associated with the c.1229del variant (PMID: 23946381). The c.1229del variant has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). Based on the available evidence, the c.1229del (p.Thr410MetfsTer15) variant is classified as Pathogenic.

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

Last Updated: Nov 3, 2024

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