NM_007194.4(CHEK2):c.1160C>G (p.Thr387Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 15, 2021
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:: RCV000222039.7

Allele description [Variation Report for NM_007194.4(CHEK2):c.1160C>G (p.Thr387Ser)]

NM_007194.4(CHEK2):c.1160C>G (p.Thr387Ser)

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.1160C>G (p.Thr387Ser)

HGVS:

NC_000022.11:g.28695809G>C
NG_008150.2:g.51058C>G
NM_001005735.2:c.1289C>G
NM_001257387.2:c.497C>G
NM_001349956.2:c.959C>G
NM_007194.4:c.1160C>GMANE SELECT
NM_145862.2:c.1073C>G
NP_001005735.1:p.Thr430Ser
NP_001244316.1:p.Thr166Ser
NP_001336885.1:p.Thr320Ser
NP_009125.1:p.Thr387Ser
NP_665861.1:p.Thr358Ser
LRG_302t1:c.1160C>G
LRG_302:g.51058C>G
LRG_302p1:p.Thr387Ser
NC_000022.10:g.29091797G>C
NG_008150.1:g.51026C>G
NM_007194.3:c.1160C>G

Protein change:

T166S

Links:

dbSNP: rs587780168

NCBI 1000 Genomes Browser:

rs587780168

Molecular consequence:

NM_001005735.2:c.1289C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.497C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.959C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.1160C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.1073C>G - 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
SCV000273683	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 15, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28135145, 30851065 Citation Link,
SCV001359143	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 15, 2019)	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

SCV000273683

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 15, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001359143

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 15, 2019)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S.

J Clin Oncol. 2017 Apr 1;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30.

PubMed [citation]

PMID:: 28135145
PMCID:: PMC5455355

Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system.

Delimitsou A, Fostira F, Kalfakakou D, Apostolou P, Konstantopoulou I, Kroupis C, Papavassiliou AG, Kleibl Z, Stratikos E, Voutsinas GE, Yannoukakos D.

Hum Mutat. 2019 May;40(5):631-648. doi: 10.1002/humu.23728. Epub 2019 Mar 9.

PubMed [citation]

PMID:: 30851065

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000273683.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.T387S variant (also known as c.1160C>G), located in coding exon 10 of the CHEK2 gene, results from a C to G substitution at nucleotide position 1160. The threonine at codon 387 is replaced by serine, an amino acid with similar properties. This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is highly conserved in available vertebrate species. In addition, 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

From Color Diagnostics, LLC DBA Color Health, SCV001359143.2

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

Description

This missense variant replaces threonine with serine at codon 387 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional study has shown that this variant is defective in the complementation assay for growth after DNA damage (PMID 30851065). This variant has been reported in 1 individual affected with breast cancer (PMID 30851065). This variant has been identified in 1/31410 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

Last Updated: May 1, 2024

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