NM_007194.4(CHEK2):c.85C>T (p.Gln29Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 14, 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:: RCV000167444.12

Allele description [Variation Report for NM_007194.4(CHEK2):c.85C>T (p.Gln29Ter)]

NM_007194.4(CHEK2):c.85C>T (p.Gln29Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.85C>T (p.Gln29Ter)

HGVS:

NC_000022.11:g.28734637G>A
NG_008150.2:g.12230C>T
NM_001005735.2:c.85C>T
NM_001257387.2:c.-693C>T
NM_001349956.2:c.85C>T
NM_007194.4:c.85C>TMANE SELECT
NM_145862.2:c.85C>T
NP_001005735.1:p.Gln29Ter
NP_001336885.1:p.Gln29Ter
NP_009125.1:p.Gln29Ter
NP_665861.1:p.Gln29Ter
LRG_302t1:c.85C>T
LRG_302:g.12230C>T
LRG_302p1:p.Gln29Ter
NC_000022.10:g.29130625G>A
NG_008150.1:g.12198C>T
NM_007194.3:c.85C>T
p.Q29*

Protein change:

Q29*

Links:

dbSNP: rs761494650

NCBI 1000 Genomes Browser:

rs761494650

Molecular consequence:

NM_001257387.2:c.-693C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.85C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001349956.2:c.85C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_007194.4:c.85C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_145862.2:c.85C>T - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000218300	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 14, 2024)	germline	clinical testing	Citation Link,
SCV000292166	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28008555, 28873162, 33471991, 33919281, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000218300

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 14, 2024)

germline

clinical testing

Citation Link,

SCV000292166

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 2, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results.

Pritzlaff M, Summerour P, McFarland R, Li S, Reineke P, Dolinsky JS, Goldgar DE, Shimelis H, Couch FJ, Chao EC, LaDuca H.

Breast Cancer Res Treat. 2017 Feb;161(3):575-586. doi: 10.1007/s10549-016-4085-4. Epub 2016 Dec 22.

PubMed [citation]

PMID:: 28008555
PMCID:: PMC5241330

Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A, Pradhan N, Arnold A, Walsh MF, Li Y, Balakrishnan AR, Syed A, Prasad M, Nafa K, Carlo MI, Cadoo KA, Sheehan M, Fleischut MH, Salo-Mullen E, Trottier M, Lipkin SM, Lincoln A, et al.

JAMA. 2017 Sep 5;318(9):825-835. doi: 10.1001/jama.2017.11137. Erratum in: JAMA. 2018 Dec 11;320(22):2381. doi: 10.1001/jama.2018.17511.

PubMed [citation]

PMID:: 28873162
PMCID:: PMC5611881

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000218300.9

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

Description

The p.Q29* pathogenic mutation (also known as c.85C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 85. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been identified in a patient with male breast cancer and in an individual with ovarian cancer (Pritzlaff M et al. Breast Cancer Res Treat. 2016 02;161(3):575-586; Harter P et al. PLoS One 2017 Oct;12(10):e0186043). 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

From Color Diagnostics, LLC DBA Color Health, SCV000292166.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant changes 1 nucleotide in exon 2 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer (PMID: 28008555, 33919281) and in an individual with prostate cancer (PMID: 28873162). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases, 0/53461 unaffected controls (PMID: 33471991;Leiden Open Variation Database DB-ID CHEK2_000237). This variant has also been identified in 2/249444 chromosomes 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

Last Updated: Oct 20, 2024

ClinVar

Relating variation to medicine