VCV000126908.22 - ClinVar

NM_007194.4(CHEK2):c.1201A>G (p.Thr401Ala)

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.

(10)

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.1201A>G (p.Thr401Ala)

Variation ID: 126908 Accession: VCV000126908.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.1 22: 28695768 (GRCh38) [ NCBI UCSC ] 22: 29091756 (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	Apr 24, 2014	Aug 25, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007194.4:c.1201A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009125.1:p.Thr401Ala	missense
NM_001005735.2:c.1330A>G	NP_001005735.1:p.Thr444Ala	missense
NM_001257387.2:c.538A>G	NP_001244316.1:p.Thr180Ala	missense
NM_001349956.2:c.1000A>G	NP_001336885.1:p.Thr334Ala	missense
NM_145862.2:c.1114A>G	NP_665861.1:p.Thr372Ala	missense
NC_000022.11:g.28695768T>C
NC_000022.10:g.29091756T>C
NG_008150.2:g.51099A>G
LRG_302:g.51099A>G
LRG_302t1:c.1201A>G	LRG_302p1:p.Thr401Ala

... more HGVS ... less HGVS

Protein change

T401A, T334A, T372A, T180A, T444A

Other names

chr22:29,091,756T>C
p.T401A:ACT>GCT

Canonical SPDI

NC_000022.11:28695767: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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA230680 dbSNP: rs121908704 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.
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	May 27, 2022	RCV000114764.7
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 2, 2023	RCV000115988.15
Familial cancer of breast	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Jan 10, 2024	RCV000232135.15
not specified	Uncertain significance (1)	criteria provided, single submitter	Jul 31, 2024	RCV004595927.1

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 (Nov 12, 2021)	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: SCV000689639.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 26506619‚ 30851065 Comment: This missense variant replaces threonine with alanine at codon 401 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces threonine with alanine at codon 401 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). A functional study has shown this variant to result in partial loss of CHEK2 function (PMID: 30851065). This variant has been reported in an individual affected with non-Hodgkin lymphoma (PMID: 26506619). This variant has been identified in 4/250994 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 (Mar 02, 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: SCV000216637.8 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 30851065 Comment: The p.T401A variant (also known as c.1201A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide … (more) The p.T401A variant (also known as c.1201A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1201. The threonine at codon 401 is replaced by alanine, an amino acid with similar properties. This alteration behaved as semi-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is 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 (Sep 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217537.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197495.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Uncertain significance (Mar 28, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785056.2 First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018	Publications: PubMed (1) PubMed: 26506619
Uncertain significance (Apr 01, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149897.16 First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023	Comment: Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; … (more) Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with non-Hodgkin lymphoma (Havranek 2015); Published functional studies are inconclusive: intermediate DNA damage response in in vivo yeast-based assays (Delimitsou 2019); This variant is associated with the following publications: (PMID: 26506619, 30851065) (less)
Uncertain significance (Mar 09, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004020213.1 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 (Jan 10, 2024)	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: SCV000289654.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 28492532‚ 26506619‚ 30851065 Comment: This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 401 of the CHEK2 protein (p.Thr401Ala). … (more) This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 401 of the CHEK2 protein (p.Thr401Ala). This variant is present in population databases (rs121908704, gnomAD 0.004%). This missense change has been observed in individual(s) with non-Hodgkin lymphoma, and breast cancer (PMID: 26506619, 30851065). ClinVar contains an entry for this variant (Variation ID: 126908). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065). 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 (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005089754.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: germline	Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague Accession: SCV000148659.1 First in ClinVar: Apr 24, 2014 Last updated: Apr 24, 2014 Comment: Characterized in 1 out of 340 Non-Hodgkin lymphoma patients.

Comment:

This missense variant replaces threonine with alanine at codon 401 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). A functional study has shown this variant to result in partial loss of CHEK2 function (PMID: 30851065). This variant has been reported in an individual affected with non-Hodgkin lymphoma (PMID: 26506619). This variant has been identified in 4/250994 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 p.T401A variant (also known as c.1201A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1201. The threonine at codon 401 is replaced by alanine, an amino acid with similar properties. This alteration behaved as semi-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is 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:

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with non-Hodgkin lymphoma (Havranek 2015); Published functional studies are inconclusive: intermediate DNA damage response in in vivo yeast-based assays (Delimitsou 2019); This variant is associated with the following publications: (PMID: 26506619, 30851065)

Comment:

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 401 of the CHEK2 protein (p.Thr401Ala). This variant is present in population databases (rs121908704, gnomAD 0.004%). This missense change has been observed in individual(s) with non-Hodgkin lymphoma, and breast cancer (PMID: 26506619, 30851065). ClinVar contains an entry for this variant (Variation ID: 126908). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065). 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

Title	Author	Journal	Year	Link
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system.	Delimitsou A	Human mutation	2019	PMID: 30851065
Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma.	Havranek O	PloS one	2015	PMID: 26506619

Text-mined citations for rs121908704 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_007194.4(CHEK2):c.1201A>G (p.Thr401Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908704 ...