NM_007194.4(CHEK2):c.157T>A (p.Ser53Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 19, 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:: RCV000132037.23

Allele description [Variation Report for NM_007194.4(CHEK2):c.157T>A (p.Ser53Thr)]

NM_007194.4(CHEK2):c.157T>A (p.Ser53Thr)

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.157T>A (p.Ser53Thr)

HGVS:

NC_000022.11:g.28734565A>T
NG_008150.2:g.12302T>A
NM_001005735.2:c.157T>A
NM_001257387.2:c.-621T>A
NM_001349956.2:c.157T>A
NM_007194.4:c.157T>AMANE SELECT
NM_145862.2:c.157T>A
NP_001005735.1:p.Ser53Thr
NP_001336885.1:p.Ser53Thr
NP_009125.1:p.Ser53Thr
NP_665861.1:p.Ser53Thr
LRG_302t1:c.157T>A
LRG_302:g.12302T>A
LRG_302p1:p.Ser53Thr
NC_000022.10:g.29130553A>T
NG_008150.1:g.12270T>A
NM_007194.3:c.157T>A
p.S53T

Protein change:

S53T

Links:

dbSNP: rs371657037

NCBI 1000 Genomes Browser:

rs371657037

Molecular consequence:

NM_001257387.2:c.-621T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.157T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.157T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.157T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.157T>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
SCV000187096	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 19, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32658311, 33471991, 37449874 Citation Link,
SCV000684610	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 24, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24728327, 32658311, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000187096

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 19, 2024)

germline

clinical testing

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

Citation Link,

SCV000684610

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 24, 2023)

germline

clinical testing

PubMed (4)
[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

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

Stolarova L, Kleiblova P, Zemankova P, Stastna B, Janatova M, Soukupova J, Achatz MI, Ambrosone C, Apostolou P, Arun BK, Auer P, Barnard M, Bertelsen B; Biobank Japan., Blok MJ, Boddicker N, Brunet J, Burnside ES, Calvello M, Campbell I, Chan SH, Chen F, et al.

Clin Cancer Res. 2023 Aug 15;29(16):3037-3050. doi: 10.1158/1078-0432.CCR-23-0212.

PubMed [citation]

PMID:: 37449874
PMCID:: PMC10425727

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]

PMID:: 24728327
PMCID:: PMC3984285

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000187096.9

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

Description

The p.S53T variant (also known as c.157T>A), located in coding exon 1 of the CHEK2 gene, results from a T to A substitution at nucleotide position 157. The serine at codon 53 is replaced by threonine, an amino acid with similar properties. This alteration was detected by genome sequencing in an ancestrally diverse cohort of 681 healthy individuals (Bodian DL et al. PLoS One. 2014 Apr 11;9(4):e94554). This alteration was seen in 0/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). In another study, this variant was reported in 5/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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, SCV000684610.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces serine with threonine at codon 53 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian cancer (DOI: 10.26650/experimed.1187969) or breast cancer (PMID: 33471991), but also in control individuals (PMID: 24728327, 32658311, 33471991). This variant has been identified in 12/251418 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: Oct 26, 2024

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