NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met) AND Breast neoplasm

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 14, 2016
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:: RCV000317389.9

Allele description [Variation Report for NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)]

NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)

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.1427C>T (p.Thr476Met)

Other names:

p.T476M:ACG>ATG

HGVS:

NC_000022.11:g.28694066G>A
NG_008150.2:g.52801C>T
NM_001005735.2:c.1556C>T
NM_001257387.2:c.764C>T
NM_001349956.2:c.1226C>T
NM_007194.4:c.1427C>TMANE SELECT
NM_145862.2:c.1340C>T
NP_001005735.1:p.Thr519Met
NP_001244316.1:p.Thr255Met
NP_001336885.1:p.Thr409Met
NP_009125.1:p.Thr476Met
NP_665861.1:p.Thr447Met
LRG_302t1:c.1427C>T
LRG_302:g.52801C>T
LRG_302p1:p.Thr476Met
NC_000022.10:g.29090054G>A
NG_008150.1:g.52769C>T
NM_001005735.1:c.1556C>T
NM_007194.3:c.1427C>T
p.T476M

Protein change:

T255M

Links:

dbSNP: rs142763740

NCBI 1000 Genomes Browser:

rs142763740

Molecular consequence:

NM_001005735.2:c.1556C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.764C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.1226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.1427C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.1340C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Breast neoplasm
Synonyms:: Neoplasm of breast; Breast tumor; Neoplasm of the breast; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0021100; MeSH: D001943; MedGen: C1458155; Human Phenotype Ontology: HP:0100013

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000437714	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Likely pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21244692, 22114986, 22419737, 22862163, 23552953, 24595525 ICSL_Variant_Classification_20161018.pdf Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000437714

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification 20161018)

Likely pathogenic
(Jun 14, 2016)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

ICSL_Variant_Classification_20161018.pdf

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

Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study.

Le Calvez-Kelm F, Lesueur F, Damiola F, Vallée M, Voegele C, Babikyan D, Durand G, Forey N, McKay-Chopin S, Robinot N, Nguyen-Dumont T, Thomas A, Byrnes GB; Breast Cancer Family Registry., Hopper JL, Southey MC, Andrulis IL, John EM, Tavtigian SV.

Breast Cancer Res. 2011 Jan 18;13(1):R6. doi: 10.1186/bcr2810.

PubMed [citation]

PMID:: 21244692
PMCID:: PMC3109572

CHEK2 contribution to hereditary breast cancer in non-BRCA families.

Desrichard A, Bidet Y, Uhrhammer N, Bignon YJ.

Breast Cancer Res. 2011;13(6):R119. doi: 10.1186/bcr3062. Epub 2011 Nov 24.

PubMed [citation]

PMID:: 22114986
PMCID:: PMC3326561

See all PubMed Citations (6)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000437714.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Across three studies, the c.1427C>T (p.Thr476Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild-type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as likely pathogenic for breast cancer.

#	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 8, 2024

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