This variant is denoted CHEK2 c.1415A>G at the cDNA level, p.Lys472Arg (K472R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys472Arg was not observed in approximately 3,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Lys472Arg occurs at a position that is not conserved and is located within the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CHEK2 Lys472Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1415A>G (p.Lys472Arg)
Germline
Classification
Help
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.
(6)
Help
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.1415A>G (p.Lys472Arg)
Variation ID: 418901 Accession: VCV000418901.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28694078 (GRCh38) [ NCBI UCSC ] 22: 29090066 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 29, 2017 May 1, 2024 Nov 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007194.4:c.1415A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Lys472Arg missense NM_001005735.2:c.1544A>G NP_001005735.1:p.Lys515Arg missense NM_001257387.2:c.752A>G NP_001244316.1:p.Lys251Arg missense NM_001349956.2:c.1214A>G NP_001336885.1:p.Lys405Arg missense NM_145862.2:c.1328A>G NP_665861.1:p.Lys443Arg missense NC_000022.11:g.28694078T>C NC_000022.10:g.29090066T>C NG_008150.2:g.52789A>G LRG_302:g.52789A>G LRG_302t1:c.1415A>G LRG_302p1:p.Lys472Arg - Protein change
- K472R, K251R, K405R, K443R, K515R
- Other names
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- Canonical SPDI
- NC_000022.11:28694077:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| 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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 13, 2016 | RCV000478318.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 17, 2023 | RCV000537431.8 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000708695.9 |
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. |
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|---|---|---|---|---|---|
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Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821991.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
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Uncertain significance
(Jul 13, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000566297.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
This variant is denoted CHEK2 c.1415A>G at the cDNA level, p.Lys472Arg (K472R) at the protein level, and results in the change of a Lysine to … (more)
This variant is denoted CHEK2 c.1415A>G at the cDNA level, p.Lys472Arg (K472R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys472Arg was not observed in approximately 3,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Lys472Arg occurs at a position that is not conserved and is located within the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CHEK2 Lys472Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
|
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Uncertain significance
(Aug 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000910219.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces lysine with arginine at codon 472 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 472 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). 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 not been identified 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)
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Uncertain significance
(Nov 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000633133.6
First in ClinVar: Dec 26, 2017 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 472 of the CHEK2 protein (p.Lys472Arg). … (more)
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 472 of the CHEK2 protein (p.Lys472Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 418901). 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 disruptive. 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)
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Uncertain significance
(Sep 25, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002537371.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1415A>G (p.K472R) variant has been reported in 1 individual with a personal or family history of breast and/or ovarian cancer (PMID 31159747). This … (more)
The CHEK2 c.1415A>G (p.K472R) variant has been reported in 1 individual with a personal or family history of breast and/or ovarian cancer (PMID 31159747). This variant was not observed in in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 418901). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004092476.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The p.K472R variant (also known as c.1415A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide … (more)
The p.K472R variant (also known as c.1415A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1415. The lysine at codon 472 is replaced by arginine, an amino acid with highly similar properties. This alteration was 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
Comment:
Comment:
This missense variant replaces lysine with arginine at codon 472 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). 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 not been identified 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:
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 472 of the CHEK2 protein (p.Lys472Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 418901). 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 disruptive. 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.
Comment:
The p.K472R variant (also known as c.1415A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1415. The lysine at codon 472 is replaced by arginine, an amino acid with highly similar properties. This alteration was 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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:
This variant is denoted CHEK2 c.1415A>G at the cDNA level, p.Lys472Arg (K472R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys472Arg was not observed in approximately 3,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Lys472Arg occurs at a position that is not conserved and is located within the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CHEK2 Lys472Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Comment:
This missense variant replaces lysine with arginine at codon 472 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). 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 not been identified 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:
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 472 of the CHEK2 protein (p.Lys472Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 418901). 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 disruptive. 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.
Comment:
The p.K472R variant (also known as c.1415A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1415. The lysine at codon 472 is replaced by arginine, an amino acid with highly similar properties. This alteration was 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. | Stolarova L | Clinical cancer research : an official journal of the American Association for Cancer Research | 2023 | PMID: 37449874 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Text-mined citations for rs1064793511 ...
HelpThese 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 Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.