NM_007194.4(CHEK2):c.253C>T (p.Pro85Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 22, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001015877.3

Allele description [Variation Report for NM_007194.4(CHEK2):c.253C>T (p.Pro85Ser)]

NM_007194.4(CHEK2):c.253C>T (p.Pro85Ser)

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.253C>T (p.Pro85Ser)

HGVS:

NC_000022.11:g.28734469G>A
NG_008150.2:g.12398C>T
NM_001005735.2:c.253C>T
NM_001257387.2:c.-525C>T
NM_001349956.2:c.253C>T
NM_007194.4:c.253C>TMANE SELECT
NM_145862.2:c.253C>T
NP_001005735.1:p.Pro85Ser
NP_001336885.1:p.Pro85Ser
NP_009125.1:p.Pro85Ser
NP_665861.1:p.Pro85Ser
LRG_302t1:c.253C>T
LRG_302:g.12398C>T
LRG_302p1:p.Pro85Ser
NC_000022.10:g.29130457G>A
NC_000022.10:g.29130457G>A
NG_008150.1:g.12366C>T
NM_007194.3:c.253C>T

Protein change:

P85S

Links:

dbSNP: rs1366081066

NCBI 1000 Genomes Browser:

rs1366081066

Molecular consequence:

NM_001257387.2:c.-525C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.253C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.253C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.253C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.253C>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
SCV001176763	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 22, 2024)	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

SCV001176763

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 22, 2024)

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

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

Details of each submission

From Ambry Genetics, SCV001176763.4

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

Description

The p.P85S variant (also known as c.253C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 253. The proline at codon 85 is replaced by serine, an amino acid with similar properties. 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;29:3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, 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: Sep 29, 2024

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