NM_007194.4(CHEK2):c.1133C>T (p.Thr378Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 20, 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:: RCV000115984.19

Allele description [Variation Report for NM_007194.4(CHEK2):c.1133C>T (p.Thr378Ile)]

NM_007194.4(CHEK2):c.1133C>T (p.Thr378Ile)

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.1133C>T (p.Thr378Ile)

Other names:

p.T378I:ACC>ATC

HGVS:

NC_000022.11:g.28695836G>A
NG_008150.2:g.51031C>T
NM_001005735.2:c.1262C>T
NM_001257387.2:c.470C>T
NM_001349956.2:c.932C>T
NM_007194.4:c.1133C>TMANE SELECT
NM_145862.2:c.1046C>T
NP_001005735.1:p.Thr421Ile
NP_001244316.1:p.Thr157Ile
NP_001336885.1:p.Thr311Ile
NP_009125.1:p.Thr378Ile
NP_665861.1:p.Thr349Ile
LRG_302t1:c.1133C>T
LRG_302:g.51031C>T
LRG_302p1:p.Thr378Ile
NC_000022.10:g.29091824G>A
NG_008150.1:g.50999C>T
NM_007194.3:c.1133C>T
p.T378I

Protein change:

T157I

Links:

dbSNP: rs587780167

NCBI 1000 Genomes Browser:

rs587780167

Molecular consequence:

NM_001005735.2:c.1262C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.470C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.932C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.1133C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.1046C>T - 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
SCV000186773	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Jul 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000537537	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 20, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17698850, 20713355, 30851065, 33471991, 25741868
SCV002537025	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Aug 21, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 33471991, 30851065 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186773

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Jul 20, 2023)

germline

clinical testing

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

Citation Link,

SCV000537537

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 20, 2022)

germline

clinical testing

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

SCV002537025

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Aug 21, 2021)

germline

curation

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

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, curation

Citations

PubMed

Human T-cell leukemia virus type 1 Tax oncoprotein prevents DNA damage-induced chromatin egress of hyperphosphorylated Chk2.

Gupta SK, Guo X, Durkin SS, Fryrear KF, Ward MD, Semmes OJ.

J Biol Chem. 2007 Oct 5;282(40):29431-40. Epub 2007 Aug 13.

PubMed [citation]

PMID:: 17698850

Interdependent phosphorylation within the kinase domain T-loop Regulates CHK2 activity.

Guo X, Ward MD, Tiedebohl JB, Oden YM, Nyalwidhe JO, Semmes OJ.

J Biol Chem. 2010 Oct 22;285(43):33348-33357. doi: 10.1074/jbc.M110.149609. Epub 2010 Aug 16.

PubMed [citation]

PMID:: 20713355
PMCID:: PMC2963420

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000186773.8

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

Description

The p.T378I variant (also known as c.1133C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1133. The threonine at codon 378 is replaced by isoleucine, an amino acid with similar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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, SCV000537537.6

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

Description

This missense variant replaces threonine with isoleucine at codon 378 in the kinase domain of the CHEK2 protein. The reference threonine residue has been shown to be phosphorylated in response to DNA damage stimuli (PMID: 17698850, 20713355) and to play a role in regulating ionizing radiation-induced kinase activity (PMID: 20713355). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to be functional in DNA damage repair assay in yeast (PMID: 30851065). In a large breast cancer case-control study, this variant was observed in 9/60466 cases and 7/53461 unaffected controls (OR=1.137, 95%CI 0.423 to 3.053, p-value=1) (PMID: 33471991, Leiden Open Variation Database DB-ID CHEK2_000355). This variant has been identified in 13/250714 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 Sema4, Sema4, SCV002537025.1

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

#	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: Mar 16, 2024

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