NM_007194.4(CHEK2):c.100_101del (p.Gln34fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 7, 2024
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:: RCV003584876.2

Allele description [Variation Report for NM_007194.4(CHEK2):c.100_101del (p.Gln34fs)]

NM_007194.4(CHEK2):c.100_101del (p.Gln34fs)

Gene:

CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.100_101del (p.Gln34fs)

HGVS:

NC_000022.11:g.28734621TG[1]
NG_008150.2:g.12243CA[1]
NM_001005735.2:c.100_101del
NM_001257387.2:c.-680CA[1]
NM_001349956.2:c.100_101del
NM_007194.4:c.100_101delMANE SELECT
NM_145862.2:c.100_101del
NP_001005735.1:p.Gln34fs
NP_001336885.1:p.Gln34fs
NP_009125.1:p.Gln34fs
NP_665861.1:p.Gln34fs
LRG_302t1:c.100_101del
LRG_302:g.12243CA[1]
LRG_302p1:p.Gln34fs
NC_000022.10:g.29130609TG[1]
NC_000022.10:g.29130609_29130610del
NG_008150.1:g.12211CA[1]
NM_007194.3:c.100_101delCA

Protein change:

Q34fs

Links:

dbSNP: rs2054330803

NCBI 1000 Genomes Browser:

rs2054330803

Molecular consequence:

NM_001257387.2:c.-680CA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.100_101del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001349956.2:c.100_101del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_007194.4:c.100_101del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_145862.2:c.100_101del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004361414	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005024887	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004361414

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 26, 2022)

germline

clinical testing

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

SCV005024887

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 7, 2024)

germline

clinical testing

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

Citation Link

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

Citations

PubMed

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

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer.

Kleiblova P, Stolarova L, Krizova K, Lhota F, Hojny J, Zemankova P, Havranek O, Vocka M, Cerna M, Lhotova K, Borecka M, Janatova M, Soukupova J, Sevcik J, Zimovjanova M, Kotlas J, Panczak A, Vesela K, Cervenkova J, Schneiderova M, Burocziova M, Burdova K, et al.

Int J Cancer. 2019 Oct 1;145(7):1782-1797. doi: 10.1002/ijc.32385. Epub 2019 May 20.

PubMed [citation]

PMID:: 31050813

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004361414.1

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

Description

This variant deletes 2 nucleotides in exon 2 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified 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

From Ambry Genetics, SCV005024887.1

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

Description

The c.100_101delCA pathogenic mutation, located in coding exon 1 of the CHEK2 gene, results from a deletion of two nucleotides at nucleotide positions 100 to 101, causing a translational frameshift with a predicted alternate stop codon (p.Q34Vfs*42). This variant has been reported in 1 of 1928 individuals with breast and/or ovarian cancer and 0 of 3360 healthy controls (Kleiblova P et al. Int J Cancer, 2019 Oct;145:1782-1797). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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: Sep 29, 2024

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