NM_007194.4(CHEK2):c.176C>A (p.Thr59Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 17, 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:: RCV000130842.19

Allele description [Variation Report for NM_007194.4(CHEK2):c.176C>A (p.Thr59Lys)]

NM_007194.4(CHEK2):c.176C>A (p.Thr59Lys)

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.176C>A (p.Thr59Lys)

HGVS:

NC_000022.11:g.28734546G>T
NG_008150.2:g.12321C>A
NM_001005735.2:c.176C>A
NM_001257387.2:c.-602C>A
NM_001349956.2:c.176C>A
NM_007194.4:c.176C>AMANE SELECT
NM_145862.2:c.176C>A
NP_001005735.1:p.Thr59Lys
NP_001336885.1:p.Thr59Lys
NP_009125.1:p.Thr59Lys
NP_665861.1:p.Thr59Lys
LRG_302t1:c.176C>A
LRG_302:g.12321C>A
LRG_302p1:p.Thr59Lys
NC_000022.10:g.29130534G>T
NG_008150.1:g.12289C>A
NM_007194.3:c.176C>A
O96017:p.Thr59Lys
p.T59K

Protein change:

T59K

Links:

UniProtKB: O96017#VAR_026630; dbSNP: rs149991239

NCBI 1000 Genomes Browser:

rs149991239

Molecular consequence:

NM_001257387.2:c.-602C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.176C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.176C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.176C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.176C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000684616	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12052256, 22419737, 25741868
SCV001173628	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 15, 2022)	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

SCV000684616

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 17, 2023)

germline

clinical testing

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

SCV001173628

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 15, 2022)

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

Mutation analysis of the CHK2 gene in breast carcinoma and other cancers.

Ingvarsson S, Sigbjornsdottir BI, Huiping C, Hafsteinsdottir SH, Ragnarsson G, Barkardottir RB, Arason A, Egilsson V, Bergthorsson JT.

Breast Cancer Res. 2002;4(3):R4. Epub 2002 Mar 20.

PubMed [citation]

PMID:: 12052256
PMCID:: PMC111029

Response to DNA damage of CHEK2 missense mutations in familial breast cancer.

Roeb W, Higgins J, King MC.

Hum Mol Genet. 2012 Jun 15;21(12):2738-44. doi: 10.1093/hmg/dds101. Epub 2012 Mar 13.

PubMed [citation]

PMID:: 22419737
PMCID:: PMC3363333

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000684616.5

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

Description

This missense variant replaces threonine with lysine at codon 59 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A yeast-based complementation assay has shown that this variant protein partially impacts DNA damage response compared with wild-type protein (PMID: 22419737). This variant has been reported in individuals affected with breast, colorectal, stomach, and ovarian cancer (PMID: 12052256). This variant has also been identified in 4/251456 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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, SCV001173628.5

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

Description

The p.T59K variant (also known as c.176C>A), located in coding exon 1 of the CHEK2 gene, results from a C to A substitution at nucleotide position 176. The threonine at codon 59 is replaced by lysine, an amino acid with similar properties. In a large Icelandic study assessing breast tumors for loss of heterozygosity at the CHEK2 gene locus, this alteration was identified as a germline mutation in 9 individuals with cancer across 5 families, including individuals with breast, colon, ovarian, stomach, gastric, prostate and thyroid cancer. Some of these individuals had multiple primary cancers, and the youngest breast cancer diagnosis was at age 29. In total, this alteration segregated with cancer in 9 of 11 individuals with cancer across these 5 families. This alteration was absent in six individuals without a history of cancer in one of these families, and it was absent in 452 control subjects. Authors concluded that this may be a low penetrance cancer susceptibility allele (Ingvarsson S et al. Breast Cancer Res. 2002;4:R4). Another research group subsequently developed a yeast-based assay to assess in vivo CHEK2- mediated response to DNA damage and determined that this allele had an intermediate or partial loss of DNA damage response compared to that mediated by wild-type CHEK2 alleles (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). In addition, this alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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

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