VCV002583585.3 - ClinVar

NM_007194.4(CHEK2):c.1018G>T (p.Glu340Ter)

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.

(2)

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.

Pathogenic

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.1018G>T (p.Glu340Ter)

Variation ID: 2583585 Accession: VCV002583585.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.1 22: 28696978 (GRCh38) [ NCBI UCSC ] 22: 29092966 (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 21, 2023	Feb 14, 2024	Sep 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_007194.4:c.1018G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009125.1:p.Glu340Ter	nonsense
NM_001005735.2:c.1147G>T	NP_001005735.1:p.Glu383Ter	nonsense
NM_001257387.2:c.355G>T	NP_001244316.1:p.Glu119Ter	nonsense
NM_001349956.2:c.817G>T	NP_001336885.1:p.Glu273Ter	nonsense
NM_145862.2:c.1009-1105G>T		intron variant
NC_000022.11:g.28696978C>A
NC_000022.10:g.29092966C>A
NG_008150.2:g.49889G>T
LRG_302:g.49889G>T
LRG_302t1:c.1018G>T	LRG_302p1:p.Glu340Ter

... more HGVS ... less HGVS

Protein change

E119*, E273*, E340*, E383*

Other names

Canonical SPDI

NC_000022.11:28696977:C:A

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.

Links

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.
Familial cancer of breast	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 10, 2023	RCV003334507.4

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 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.
Pathogenic (Jun 27, 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: SCV004042909.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Sep 10, 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: SCV004298844.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 21876083‚ 24713400‚ 28724667 Comment: For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Glu340) in the CHEK2 gene. It … (more) For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Glu340) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Glu340*) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667).

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
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland.	Bąk A	Hereditary cancer in clinical practice	2014	PMID: 24713400
Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer.	Cybulski C	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2011	PMID: 21876083

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_007194.4(CHEK2):c.1018G>T (p.Glu340Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...