The frequency of this variant in the general population, 0.00012 (14/113274 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMIDs: 32906215 (2020), 28779002 (2017), 17100999 (2006), 31206626 (2019)) and colorectal cancer (PMIDs: 17100999 (2006), 28944238 (2017)). In a large-scale breast cancer association study, the variant was observed among the breast cancer cases and in healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). This variant has also been reported to have a benign effect on CHEK2 cell growth in a yeast based system, however other critical CHEK2 protein functions were not assessed (PMID: 30851065 (2019)). 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.
ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1215C>A (p.Asn405Lys)
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.
(11)
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.
Conflicting classifications of pathogenicity
Uncertain significance(10); Likely benign(1)
Uncertain significance(10); Likely benign(1)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007194.4(CHEK2):c.1215C>A (p.Asn405Lys)
Variation ID: 128050 Accession: VCV000128050.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q12.1 22: 28695754 (GRCh38) [ NCBI UCSC ] 22: 29091742 (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 Oct 9, 2016 Oct 20, 2024 Jul 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007194.4:c.1215C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Asn405Lys missense NM_001005735.2:c.1344C>A NP_001005735.1:p.Asn448Lys missense NM_001257387.2:c.552C>A NP_001244316.1:p.Asn184Lys missense NM_001349956.2:c.1014C>A NP_001336885.1:p.Asn338Lys missense NM_145862.2:c.1128C>A NP_665861.1:p.Asn376Lys missense NC_000022.11:g.28695754G>T NC_000022.10:g.29091742G>T NG_008150.2:g.51113C>A LRG_302:g.51113C>A LRG_302t1:c.1215C>A LRG_302p1:p.Asn405Lys - Protein change
- N405K, N338K, N376K, N184K, N448K
- Other names
-
p.N405K:AAC>AAA
- Canonical SPDI
- NC_000022.11:28695753:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
- 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. |
|||
| 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 (3) |
criteria provided, multiple submitters, no conflicts
|
May 17, 2024 | RCV000115989.19 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Oct 19, 2022 | RCV000219945.12 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 6, 2024 | RCV000199599.21 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000764373.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 9, 2024 | RCV004764764.1 |
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
(Jul 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806863.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
|
|
|
Uncertain significance
(Mar 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888100.3
First in ClinVar: Sep 13, 2018 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00012 (14/113274 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.00012 (14/113274 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMIDs: 32906215 (2020), 28779002 (2017), 17100999 (2006), 31206626 (2019)) and colorectal cancer (PMIDs: 17100999 (2006), 28944238 (2017)). In a large-scale breast cancer association study, the variant was observed among the breast cancer cases and in healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). This variant has also been reported to have a benign effect on CHEK2 cell growth in a yeast based system, however other critical CHEK2 protein functions were not assessed (PMID: 30851065 (2019)). 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. (less)
|
|
|
Uncertain significance
(Dec 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254920.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 405 of the CHEK2 protein (p.Asn405Lys). … (more)
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 405 of the CHEK2 protein (p.Asn405Lys). This variant is present in population databases (rs587780171, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or colon cancer (PMID: 17100999, 28779002). ClinVar contains an entry for this variant (Variation ID: 128050). 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. 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)
|
|
|
Uncertain significance
(Mar 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215843.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(May 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149898.18
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate a growth rate comparable to benign variants in yeast based assays (PMID: 30851065); Observed in individuals with colorectal and/or breast cancer … (more)
Published functional studies demonstrate a growth rate comparable to benign variants in yeast based assays (PMID: 30851065); Observed in individuals with colorectal and/or breast cancer (PMID: 17100999, 28779002, 28944238, 31206626); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17100999, 28944238, 28779002, 32906215, 31206626, 30851065, 22419737, 19782031) (less)
|
|
|
Uncertain significance
(Dec 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785786.2
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
|
|
Uncertain significance
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Familial prostate cancer Bone osteosarcoma Li-Fraumeni syndrome 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000895408.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Likely benign
(Dec 29, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000903066.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
|
Uncertain significance
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004020174.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
|
|
Uncertain significance
(Oct 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273093.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.N405K variant (also known as c.1215C>A), located in coding exon 10 of the CHEK2 gene, results from a C to A substitution at nucleotide … (more)
The p.N405K variant (also known as c.1215C>A), located in coding exon 10 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1215. The asparagine at codon 405 is replaced by lysine, an amino acid with similar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration has been previously identified in individuals diagnosed with breast and/or colon cancer (Brinkman H et al. Clin. Genet. 2006 Dec;70:526-9; Weitzel JN et al. Cancer, 2019 08;125:2829-2836) and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is not well 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)
|
|
|
Uncertain significance
(Jul 09, 2024)
|
criteria provided, single submitter
Method: curation
|
Hereditary breast ovarian cancer syndrome
Affected status: not provided
Allele origin:
germline
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV005374638.1
First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024 |
Comment:
According to the ACMG SVI adaptation criteria we chose this criterion: BP4 (strong benign): REVEL (aus Alamut): 0.009 ((0.003, 0.016]) --> BP4_strong (Pejaver et al., … (more)
According to the ACMG SVI adaptation criteria we chose this criterion: BP4 (strong benign): REVEL (aus Alamut): 0.009 ((0.003, 0.016]) --> BP4_strong (Pejaver et al., 2022) strength? (less)
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Comment:
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 405 of the CHEK2 protein (p.Asn405Lys). This variant is present in population databases (rs587780171, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or colon cancer (PMID: 17100999, 28779002). ClinVar contains an entry for this variant (Variation ID: 128050). 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. 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:
Published functional studies demonstrate a growth rate comparable to benign variants in yeast based assays (PMID: 30851065); Observed in individuals with colorectal and/or breast cancer (PMID: 17100999, 28779002, 28944238, 31206626); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17100999, 28944238, 28779002, 32906215, 31206626, 30851065, 22419737, 19782031)
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
The p.N405K variant (also known as c.1215C>A), located in coding exon 10 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1215. The asparagine at codon 405 is replaced by lysine, an amino acid with similar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration has been previously identified in individuals diagnosed with breast and/or colon cancer (Brinkman H et al. Clin. Genet. 2006 Dec;70:526-9; Weitzel JN et al. Cancer, 2019 08;125:2829-2836) and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is not well 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.
Comment:
According to the ACMG SVI adaptation criteria we chose this criterion: BP4 (strong benign): REVEL (aus Alamut): 0.009 ((0.003, 0.016]) --> BP4_strong (Pejaver et al., 2022) strength?
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:
The frequency of this variant in the general population, 0.00012 (14/113274 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMIDs: 32906215 (2020), 28779002 (2017), 17100999 (2006), 31206626 (2019)) and colorectal cancer (PMIDs: 17100999 (2006), 28944238 (2017)). In a large-scale breast cancer association study, the variant was observed among the breast cancer cases and in healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). This variant has also been reported to have a benign effect on CHEK2 cell growth in a yeast based system, however other critical CHEK2 protein functions were not assessed (PMID: 30851065 (2019)). 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.
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 405 of the CHEK2 protein (p.Asn405Lys). This variant is present in population databases (rs587780171, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or colon cancer (PMID: 17100999, 28779002). ClinVar contains an entry for this variant (Variation ID: 128050). 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. 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:
Published functional studies demonstrate a growth rate comparable to benign variants in yeast based assays (PMID: 30851065); Observed in individuals with colorectal and/or breast cancer (PMID: 17100999, 28779002, 28944238, 31206626); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17100999, 28944238, 28779002, 32906215, 31206626, 30851065, 22419737, 19782031)
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
The p.N405K variant (also known as c.1215C>A), located in coding exon 10 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1215. The asparagine at codon 405 is replaced by lysine, an amino acid with similar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration has been previously identified in individuals diagnosed with breast and/or colon cancer (Brinkman H et al. Clin. Genet. 2006 Dec;70:526-9; Weitzel JN et al. Cancer, 2019 08;125:2829-2836) and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is not well 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.
Comment:
According to the ACMG SVI adaptation criteria we chose this criterion: BP4 (strong benign): REVEL (aus Alamut): 0.009 ((0.003, 0.016]) --> BP4_strong (Pejaver et al., 2022) strength?
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients. | Vargas-Parra G | Human mutation | 2020 | PMID: 32906215 |
| Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. | Weitzel JN | Cancer | 2019 | PMID: 31206626 |
| Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
| Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
| Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
| Evidence against a major genetic basis for combined breast and colorectal cancer susceptibility. | Brinkman H | Clinical genetics | 2006 | PMID: 17100999 |
Text-mined citations for rs587780171 ...
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 Oct 20, 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.