VCV000232215.22 - ClinVar

NM_007194.4(CHEK2):c.1391A>G (p.Lys464Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_007194.4(CHEK2):c.1391A>G (p.Lys464Arg)

Variation ID: 232215 Accession: VCV000232215.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.1 22: 28694102 (GRCh38) [ NCBI UCSC ] 22: 29090090 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2016	May 1, 2024	Dec 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_007194.4:c.1391A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009125.1:p.Lys464Arg	missense
NM_001005735.2:c.1520A>G	NP_001005735.1:p.Lys507Arg	missense
NM_001257387.2:c.728A>G	NP_001244316.1:p.Lys243Arg	missense
NM_001349956.2:c.1190A>G	NP_001336885.1:p.Lys397Arg	missense
NM_145862.2:c.1304A>G	NP_665861.1:p.Lys435Arg	missense
NC_000022.11:g.28694102T>C
NC_000022.10:g.29090090T>C
NG_008150.2:g.52765A>G
LRG_302:g.52765A>G
LRG_302t1:c.1391A>G	LRG_302p1:p.Lys464Arg

... more HGVS ... less HGVS

Protein change

K464R, K397R, K435R, K507R, K243R

Other names

Canonical SPDI

NC_000022.11:28694101:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA10581031 dbSNP: rs529571124 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CHEK2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4053	4109

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 28, 2023	RCV000222336.8
Familial cancer of breast	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 29, 2023	RCV001222736.11
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 22, 2022	RCV001753667.4
CHEK2-related disorder	Uncertain significance (1)	criteria provided, single submitter	May 18, 2023	RCV004529377.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Feb 28, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000276288.8 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Comment: The p.K464R variant (also known as c.1391A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide … (more) The p.K464R variant (also known as c.1391A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1391. The lysine at codon 464 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jul 13, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001345814.2 First in ClinVar: Mar 25, 2020 Last updated: Jun 19, 2021	Comment: This missense variant replaces lysine with arginine at codon 464 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces lysine with arginine at codon 464 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools indicate that this variant may activate a cryptic acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/233754 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. (less)
Uncertain significance (Oct 08, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002005556.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
Uncertain significance (May 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CHEK2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004109596.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The CHEK2 c.1391A>G variant is predicted to result in the amino acid substitution p.Lys464Arg. To our knowledge, this variant has not been reported in the … (more) The CHEK2 c.1391A>G variant is predicted to result in the amino acid substitution p.Lys464Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 2 of ~234,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/22-29090090-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/232215/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Jun 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217670.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Sep 22, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004221725.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000086 (2/233754 chromosomes, http://gnomad.broadinstitute.org), is uninformative … (more) The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000086 (2/233754 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on CHEK2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Dec 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001394852.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Comment: This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 464 of the CHEK2 protein (p.Lys464Arg). … (more) This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 464 of the CHEK2 protein (p.Lys464Arg). This variant is present in population databases (rs529571124, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 232215). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

The p.K464R variant (also known as c.1391A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1391. The lysine at codon 464 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces lysine with arginine at codon 464 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools indicate that this variant may activate a cryptic acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/233754 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.

Comment:

The CHEK2 c.1391A>G variant is predicted to result in the amino acid substitution p.Lys464Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 2 of ~234,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/22-29090090-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/232215/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000086 (2/233754 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on CHEK2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 464 of the CHEK2 protein (p.Lys464Arg). This variant is present in population databases (rs529571124, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 232215). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs529571124 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_007194.4(CHEK2):c.1391A>G (p.Lys464Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs529571124 ...