NM_007194.4(CHEK2):c.663C>G (p.Ile221Met) AND Predisposition to cancer

Germline classification:: Likely benign (1 submission)
Last evaluated:: Sep 14, 2023
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:: RCV001543106.4

Allele description [Variation Report for NM_007194.4(CHEK2):c.663C>G (p.Ile221Met)]

NM_007194.4(CHEK2):c.663C>G (p.Ile221Met)

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.663C>G (p.Ile221Met)

Other names:

p.I221M:ATC>ATG

HGVS:

NC_000022.11:g.28719415G>C
NG_008150.2:g.27452C>G
NM_001005735.2:c.792C>G
NM_001257387.2:c.-1C>G
NM_001349956.2:c.482+5471C>G
NM_007194.4:c.663C>GMANE SELECT
NM_145862.2:c.663C>G
NP_001005735.1:p.Ile264Met
NP_009125.1:p.Ile221Met
NP_665861.1:p.Ile221Met
LRG_302t1:c.663C>G
LRG_302:g.27452C>G
LRG_302p1:p.Ile221Met
NC_000022.10:g.29115403G>C
NM_001257387.1:c.-1C>G
NM_007194.3:c.663C>G
p.I221M

Protein change:

I221M

Links:

dbSNP: rs200451612

NCBI 1000 Genomes Browser:

rs200451612

Molecular consequence:

NM_001257387.2:c.-1C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001349956.2:c.482+5471C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001005735.2:c.792C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.663C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.663C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Predisposition to cancer
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001761613	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Likely benign (Sep 14, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001761613

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Likely benign
(Sep 14, 2023)

germline

clinical testing

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

Details of each submission

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV001761613.2

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

Description

The CHEK2 c.663C>G (p.Ile221Met) missense change has a maximum subpopulation frequency of 0.052% in gnomAD v2.1.1 and a maximum subpopulation frequency of 0.096% in gnomAD v3.2.1. The in silico tool REVEL predicts a benign effect on protein function and functional studies are in agreement with this prediction. A yeast-based growth assay indicated that this variant behaved similar to the wild-type (PMID: 30851065) and CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells also indicated that this variant behaved similar to wild-type (PMID: 37449874). Although this variant has been reported in an individual diagnosed with breast cancer prior to age 45 (PMID: 21244692), seven individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com). In summary, this variant meets criteria to be classified as likely benign.

#	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: Jan 19, 2025

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