NM_007194.4(CHEK2):c.1568G>A (p.Arg523His) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 1, 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:: RCV001569385.8

Allele description [Variation Report for NM_007194.4(CHEK2):c.1568G>A (p.Arg523His)]

NM_007194.4(CHEK2):c.1568G>A (p.Arg523His)

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.1568G>A (p.Arg523His)

HGVS:

NC_000022.11:g.28687961C>T
NG_008150.2:g.58906G>A
NM_001005735.2:c.1697G>A
NM_001257387.2:c.905G>A
NM_001349956.2:c.1367G>A
NM_007194.4:c.1568G>AMANE SELECT
NM_145862.2:c.1481G>A
NP_001005735.1:p.Arg566His
NP_001244316.1:p.Arg302His
NP_001336885.1:p.Arg456His
NP_009125.1:p.Arg523His
NP_665861.1:p.Arg494His
LRG_302t1:c.1568G>A
LRG_302:g.58906G>A
LRG_302p1:p.Arg523His
NC_000022.10:g.29083949C>T
NG_008150.1:g.58874G>A
NM_007194.3:c.1568G>A

Protein change:

R302H

Links:

dbSNP: rs948928965

NCBI 1000 Genomes Browser:

rs948928965

Molecular consequence:

NM_001005735.2:c.1697G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.1367G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.1568G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.1481G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001793451	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 1, 2024)	germline	clinical testing	Citation Link,
SCV004221732	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 25, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 33471991, 31159747, 30287823, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001793451

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 1, 2024)

germline

clinical testing

Citation Link,

SCV004221732

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Aug 25, 2023)

unknown

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]

PMID:: 31159747
PMCID:: PMC6547505

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV001793451.3

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals referred for hereditary cancer genetic testing and in a pediatric patient with a primitive neuroectodermal tumor (PMID: 31159747, 36468172); This variant is associated with the following publications: (PMID: 30287823, 36468172, 36243179, 31159747)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004221732.1

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

Description

In the published literature, this variant has been reported in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 31159747 (2019)). However, this variant has also been reported in healthy individuals (PMIDs: 30287823 (2018), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), FLOSSIES (https://whi.color.com)). The frequency of this variant in the general population, 0.0000086 (2/233408 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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