NM_007194.4(CHEK2):c.962A>C (p.Glu321Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 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:: RCV000217252.14

Allele description [Variation Report for NM_007194.4(CHEK2):c.962A>C (p.Glu321Ala)]

NM_007194.4(CHEK2):c.962A>C (p.Glu321Ala)

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.962A>C (p.Glu321Ala)

HGVS:

NC_000022.11:g.28699884T>G
NG_008150.2:g.46983A>C
NM_001005735.2:c.1091A>C
NM_001257387.2:c.299A>C
NM_001349956.2:c.761A>C
NM_007194.4:c.962A>CMANE SELECT
NM_145862.2:c.962A>C
NP_001005735.1:p.Glu364Ala
NP_001244316.1:p.Glu100Ala
NP_001336885.1:p.Glu254Ala
NP_009125.1:p.Glu321Ala
NP_665861.1:p.Glu321Ala
LRG_302t1:c.962A>C
LRG_302:g.46983A>C
LRG_302p1:p.Glu321Ala
NC_000022.10:g.29095872T>G
NG_008150.1:g.46951A>C
NM_007194.3:c.962A>C

Protein change:

E100A

Links:

dbSNP: rs374395284

NCBI 1000 Genomes Browser:

rs374395284

Molecular consequence:

NM_001005735.2:c.1091A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.299A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.761A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.962A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.962A>C - 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
SCV000276161	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35264596, 37449874 Citation Link,
SCV000689751	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 7, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276161

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 20, 2023)

germline

clinical testing

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

Citation Link,

SCV000689751

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 7, 2020)

germline

clinical testing

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

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

Detection of germline variants in Brazilian breast cancer patients using multigene panel testing.

Guindalini RSC, Viana DV, Kitajima JPFW, Rocha VM, López RVM, Zheng Y, Freitas É, Monteiro FPM, Valim A, Schlesinger D, Kok F, Olopade OI, Folgueira MAAK.

Sci Rep. 2022 Mar 9;12(1):4190. doi: 10.1038/s41598-022-07383-1.

PubMed [citation]

PMID:: 35264596
PMCID:: PMC8907244

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000276161.7

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

Description

The p.E321A variant (also known as c.962A>C), located in coding exon 8 of the CHEK2 gene, results from an A to C substitution at nucleotide position 962. The glutamic acid at codon 321 is replaced by alanine, an amino acid with dissimilar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration was also 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 deleterious 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, SCV000689751.4

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

Description

This missense variant replaces glutamic acid with alanine at codon 321 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/251484 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 20, 2024

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