ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.475T>C (p.Tyr159His)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.475T>C (p.Tyr159His)
Variation ID: 185924 Accession: VCV000185924.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28725094 (GRCh38) [ NCBI UCSC ] 22: 29121082 (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 May 29, 2016 Apr 15, 2024 Oct 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.475T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Tyr159His missense NM_001005735.2:c.604T>C NP_001005735.1:p.Tyr202His missense NM_001257387.2:c.-303T>C 5 prime UTR NM_001349956.2:c.444+149T>C intron variant NM_145862.2:c.475T>C NP_665861.1:p.Tyr159His missense NC_000022.11:g.28725094A>G NC_000022.10:g.29121082A>G NG_008150.2:g.21773T>C LRG_302:g.21773T>C LRG_302t1:c.475T>C LRG_302p1:p.Tyr159His - Protein change
- Y159H, Y202H
- Other names
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- Canonical SPDI
- NC_000022.11:28725093:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on protein interaction Variation Ontology [VariO:0058]
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3945 | 3999 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 23, 2023 | RCV000165429.13 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV000206006.17 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2018 | RCV000658932.20 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 26, 2023 | RCV001175503.5 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Oct 16, 2023 | RCV001537852.4 |
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
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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
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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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Uncertain significance
(Nov 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000785792.2
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
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Uncertain significance
(Jul 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279575.8
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
This variant is denoted CHEK2 c.475T>C at the cDNA level, p.Tyr159His (Y159H) at the protein level, and results in the change of a Tyrosine to … (more)
This variant is denoted CHEK2 c.475T>C at the cDNA level, p.Tyr159His (Y159H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAC>CAC). This variant was observed in a patient with late-onset breast cancer and another with Hodgkin lymphoma, both of whom were from the Czech Republic (Kleibl 2008, Havranek 2015). CHEK2 Tyr159His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Tyr159His occurs at a position that is conserved across species and is located in within the FHA domain (Desrichard 2011, Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Tyr159His is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000839490.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Oct 18, 2022)
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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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Invitae
Accession: SCV000262154.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 159 of the CHEK2 protein (p.Tyr159His). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 159 of the CHEK2 protein (p.Tyr159His). This variant is present in population databases (rs781254437, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer, Hodgkin's lymphoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and/or B-cell acute lymphoblastic leukemia (B-ALL) (PMID: 18058223, 21744992, 31300551). ClinVar contains an entry for this variant (Variation ID: 185924). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 33986034). 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
(Mar 08, 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:
unknown
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Myriad Genetics, Inc.
Accession: SCV004020107.1
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.
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Uncertain significance
(Jun 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001339106.2
First in ClinVar: Jun 22, 2020 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CHEK2 c.475T>C (p.Tyr159His) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain of the encoded protein sequence. Four of … (more)
Variant summary: CHEK2 c.475T>C (p.Tyr159His) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 252780 control chromosomes in gnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.475T>C has been reported in the literature in individuals affected with Breast Cancer (example: Kleibl_2008, Fostira_2019, Guindalini_2022) and an individual with myelodysplastic syndrome and leukemia (Bazinet_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report experimental evidence evaluating an impact on protein function and provided discordant results: Delimitsou_2019 suggested no damaging effect of this variant based on a Yeast functional assay, Bazinet_2021 however suggests a loss-of-function effect of this variant by a CHK2-BRCA1 colocalization assay. The following publications have been ascertained in the context of this evaluation (PMID: 33986034, 30851065, 31300551, 35264596, 18058223, 36139606, 33471991). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS: 7; Likely pathogenic: 1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 23, 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
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Ambry Genetics
Accession: SCV000216158.8
First in ClinVar: Mar 24, 2015 Last updated: Oct 28, 2023 |
Comment:
The p.Y159H variant (also known as c.475T>C), located in coding exon 3 of the CHEK2 gene, results from a T to C substitution at nucleotide … (more)
The p.Y159H variant (also known as c.475T>C), located in coding exon 3 of the CHEK2 gene, results from a T to C substitution at nucleotide position 475. The tyrosine at codon 159 is replaced by histidine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Kleibl Z et al. Breast Cancer Res. Treat. 2008 Nov;112:159-64; Fostira F et al. J Med Genet, 2020 01;57:53-61; Guindalini RSC et al. Sci Rep. 2022 Mar;12(1):4190). Additionally, this alteration was identified in an individual diagnosed with Hodgkins lymphoma and in an individual diagnosed with myelomonocytic leukemia and B-cell acute lymphoblastic leukemia (Havranek O et al. Neoplasma. 2011;58:392-5; Bazinet A et al. Cold Spring Harb Mol Case Stud, 2021 Jun;7:), and has been reported in a cohort of individuals with pancreatic cancer undergoing multigene panel testing (Puccini A et al. Cancers (Basel). 2022 Sep;14(18). Several functional studies have reported this alteration as retaining normal levels of activity (Delimitsou A et al. Hum. Mutat. 2019 May;40:631-648; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). However, another study reported that this variant impaired association with BRCA1 (Bazinet A et al. Cold Spring Harb Mol Case Stud. 2021 Jun;7(3). 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)
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Uncertain significance
(Oct 30, 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:
unknown
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Baylor Genetics
Accession: SCV004215840.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Nov 02, 2022)
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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
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684646.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces tyrosine with histidine at codon 159 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces tyrosine with histidine at codon 159 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to be functional in a yeast complementation assay (PMID: 30851065), while another functional study has shown the mutant protein to exhibit impaired binding to BRCA1 (PMID: 33986034). This variant has been reported in individuals affected with breast cancer and Hodgkin's lymphoma (PMID: 18058223, 21744992, 31300551) and in an individual who sequentially developed myelodysplastic syndrome, chronic myelomonocytic leukemia, and B-cell acute lymphoblastic leukemia (PMID: 33986034). This variant has been identified in 5/282816 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)
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Uncertain significance
(Jan 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780734.23
First in ClinVar: Jul 09, 2018 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(May 12, 2021)
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Flagged submission
flagged submission
Method: research, in vitro
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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see cases
Affected status: not applicable, yes
Allele origin:
germline,
not applicable
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Francois Mercier Lab, McGill University
Accession: SCV001593269.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
The CHEK2 c.475T>C variant leads to the amino acid change Y159H in the functionally important forkhead-associated (FHA) domain. The FHA domain appears to be critical … (more)
The CHEK2 c.475T>C variant leads to the amino acid change Y159H in the functionally important forkhead-associated (FHA) domain. The FHA domain appears to be critical for the binding to downstream BRCA1 (Li 2002). The Y159H variant is rare in population databases and is predicted as likely damaging to protein function by in silico tools. The variant is considered of uncertain significance by most laboratories and this is supported by the ACMG criteria (PM1, PM2, PP3, Richards 2015). We generated in vitro experimental evidence suggesting the Y159H variant disrupts binding to BRCA1, similarly to the I157T variant that is considered to be pathogenic by some. This consists of additional supporting level evidence for pathogenicity (Brnich 2020). These findings require validation by other laboratories but suggest the Y159H may be likely pathogenic. (less)
Observation 1:
Clinical Features:
Multiple lineage myelodysplasia (present) , Chronic myelomonocytic leukemia (present) , Precursor B-cell acute lymphoblastic leukemia (present)
Observation 2:
Comment on evidence:
We generated the Y159H protein variant using site-directed mutagenesis. The I157T and H143Y variants, as well as WT CHK2 were used as controls. In a … (more)
We generated the Y159H protein variant using site-directed mutagenesis. The I157T and H143Y variants, as well as WT CHK2 were used as controls. In a single-cell assay, we used mCherry-LacR tagged versions of these CHK2 variants tethered to a LacO array. The association between endogenous BRCA1 and CHK2 was then measured at the LacO array using an Alexa Fluor 647 anti-BRCA1 antibody. Please see Bazinet et al. 2021 (10.1101/mcs.a006090). (less)
Result:
Using a LacO-LacR system, we observed impaired protein binding of the CHK2 Y159H variant to BRCA1 compared to WT CHK2.
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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effect on protein interaction
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Francois Mercier Lab, McGill University
Accession: SCV001593269.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients. | Puccini A | Cancers | 2022 | PMID: 36139606 |
CHEK2 variants: linking functional impact to cancer risk. | Boonen RACM | Trends in cancer | 2022 | PMID: 35643632 |
Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
Common clonal origin of chronic myelomonocytic leukemia and B-cell acute lymphoblastic leukemia in a patient with a germline CHEK2 variant. | Bazinet A | Cold Spring Harbor molecular case studies | 2021 | PMID: 33986034 |
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 |
One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene. | Fostira F | Journal of medical genetics | 2020 | PMID: 31300551 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma. | Havranek O | Neoplasma | 2011 | PMID: 21744992 |
Analysis of CHEK2 FHA domain in Czech patients with sporadic breast cancer revealed distinct rare genetic alterations. | Kleibl Z | Breast cancer research and treatment | 2008 | PMID: 18058223 |
Text-mined citations for rs781254437 ...
HelpRecord last updated Apr 15, 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.