NM_007194.4(CHEK2):c.100C>T (p.Gln34Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 28, 2023
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:: RCV000584578.8

Allele description [Variation Report for NM_007194.4(CHEK2):c.100C>T (p.Gln34Ter)]

NM_007194.4(CHEK2):c.100C>T (p.Gln34Ter)

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.100C>T (p.Gln34Ter)

HGVS:

NC_000022.11:g.28734622G>A
NG_008150.2:g.12245C>T
NM_001005735.2:c.100C>T
NM_001257387.2:c.-678C>T
NM_001349956.2:c.100C>T
NM_007194.4:c.100C>TMANE SELECT
NM_145862.2:c.100C>T
NP_001005735.1:p.Gln34Ter
NP_001336885.1:p.Gln34Ter
NP_009125.1:p.Gln34Ter
NP_665861.1:p.Gln34Ter
LRG_302t1:c.100C>T
LRG_302:g.12245C>T
LRG_302p1:p.Gln34Ter
NC_000022.10:g.29130610G>A
NG_008150.1:g.12213C>T
NM_007194.3:c.100C>T

Protein change:

Q34*

Links:

dbSNP: rs1231012263

NCBI 1000 Genomes Browser:

rs1231012263

Molecular consequence:

NM_001257387.2:c.-678C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.100C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001349956.2:c.100C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_007194.4:c.100C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_145862.2:c.100C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000689625	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 914197, 33925588, 25741868
SCV001177992	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 28, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000689625

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 28, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001177992

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 28, 2022)

germline

clinical testing

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

[Cytology of reversible and irreversible epithelial changes in the uterine cervix].

Höffken H.

Fortschr Med. 1977 Oct 20;95(39):2382-6. German.

PubMed [citation]

PMID:: 914197

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects.

Apostolou P, Dellatola V, Papadimitriou C, Kalfakakou D, Fountzilas E, Faliakou E, Fountzilas G, Romanidou O, Konstantopoulou I, Fostira F.

Cancers (Basel). 2021 Apr 27;13(9). doi:pii: 2106. 10.3390/cancers13092106.

PubMed [citation]

PMID:: 33925588
PMCID:: PMC8123864

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000689625.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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. This variant has been reported in individuals affected with breast cancer (PMID: 33925588, ClinVar SCV000914197.1). 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, SCV001177992.4

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

Description

The p.Q34* pathogenic mutation (also known as c.100C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 100. This changes the amino acid from a glutamine to a stop codon within coding exon 1. 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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