VCV000231879.22 - ClinVar

NM_007194.4(CHEK2):c.1417_1428del (p.Ala473_Thr476del)

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.

(6)

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
Likely pathogenic(1); Uncertain significance(4)

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.1417_1428del (p.Ala473_Thr476del)

Variation ID: 231879 Accession: VCV000231879.22

Type and length

Deletion, 12 bp

Location

Cytogenetic: 22q12.1 22: 28694065-28694076 (GRCh38) [ NCBI UCSC ] 22: 29090053-29090064 (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	May 29, 2016	Oct 8, 2024	Sep 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007194.4:c.1417_1428del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009125.1:p.Ala473_Thr476del	inframe deletion
NM_001005735.2:c.1546_1557del	NP_001005735.1:p.Ala516_Thr519del	inframe deletion
NM_001257387.2:c.754_765del	NP_001244316.1:p.Ala252_Thr255del	inframe deletion
NM_001349956.2:c.1216_1227del	NP_001336885.1:p.Ala406_Thr409del	inframe deletion
NM_007194.3:c.1417_1428del
NM_007194.3:c.1417_1428delGCACGTTTTACG
NM_145862.2:c.1330_1341del	NP_665861.1:p.Ala444_Thr447del	inframe deletion
NC_000022.11:g.28694066_28694077del
NC_000022.10:g.29090054_29090065del
NG_008150.2:g.52791_52802del
LRG_302:g.52791_52802del
LRG_302t1:c.1417_1428del	LRG_302p1:p.Ala473_Thr476del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000022.11:28694064:CGTAAAACGTGCC: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.

Links

ClinGen: CA10577630 dbSNP: rs876659422 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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Sep 13, 2024	RCV000220927.7
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	May 23, 2022	RCV000223426.4
Familial cancer of breast	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 24, 2024	RCV000635814.12
CHEK2-related disorder	Uncertain significance (1)	no assertion criteria provided	Oct 30, 2023	RCV004532790.2

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 (Oct 28, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698775.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: Variant summary: The CHEK2 c.1417_1428delGCACGTTTTACG (p.Ala473_Thr476del) variant involves the in-frame deletion of four amino acids located in the protein-kinase domain. One in silico tool predicts … (more) Variant summary: The CHEK2 c.1417_1428delGCACGTTTTACG (p.Ala473_Thr476del) variant involves the in-frame deletion of four amino acids located in the protein-kinase domain. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 113468 control chromosomes. One reputable clinical lab has classified the variant as a VUS, while another has classified it as likely pathogenic due to functional data showing a missense variant affecting amino acid 476 to result in abolished kinase activity (Desrichard_2012) and impairment of CHEK2-mediated response to DNA damage (Roeb_2012). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a VUS - possibly pathogenic variant. (less)
Uncertain significance (Jan 24, 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: SCV000757237.7 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Comment: This variant, c.1417_1428del, results in the deletion of 4 amino acid(s) of the CHEK2 protein (p.Ala473_Thr476del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.1417_1428del, results in the deletion of 4 amino acid(s) of the CHEK2 protein (p.Ala473_Thr476del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 231879). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 (May 23, 2022)	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: SCV000275859.7 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 29522266 Comment: The c.1417_1428del12 variant (also known as p.A473_T476del) is located in coding exon 12 of the CHEK2 gene. This variant results from an in-frame GCACGTTTTACG deletion … (more) The c.1417_1428del12 variant (also known as p.A473_T476del) is located in coding exon 12 of the CHEK2 gene. This variant results from an in-frame GCACGTTTTACG deletion at nucleotide positions 1417 to 1428. This results in the in-frame deletion of 4 amino acids starting at codon 473. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). These amino acid positions are not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Likely pathogenic (Sep 13, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000278929.9 First in ClinVar: May 29, 2016 Last updated: Sep 29, 2024	Comment: In-frame deletion of 4 of amino acidsin a non-repeat region predicted to critically alter the protein; Published functional studies assessing missense variants within the deleted … (more) In-frame deletion of 4 of amino acidsin a non-repeat region predicted to critically alter the protein; Published functional studies assessing missense variants within the deleted region (p.Arg474Cys, p.Arg474His, and p.Thr476Met) demonstrate reduced or absent protein function, suggesting that loss of these residues is damaging (PMID: 22114986, 22419737, 27900359, 30851065, 31050813); Observed in individuals with personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (PMID: 29522266); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22114986, 22419737, 27900359, 30851065, 31050813, 19782031, 32805687, 29522266) (less)
Uncertain significance (Aug 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217601.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Oct 30, 2023)	no assertion criteria provided Method: clinical testing	CHEK2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004717260.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The CHEK2 c.1417_1428del12 variant is predicted to result in an in-frame deletion (p.Ala473_Thr476del). This variant may be alternatively referred to as NM_001005735.2:c.1546_1557del (p.Ala516_Thr519del). This variant … (more) The CHEK2 c.1417_1428del12 variant is predicted to result in an in-frame deletion (p.Ala473_Thr476del). This variant may be alternatively referred to as NM_001005735.2:c.1546_1557del (p.Ala516_Thr519del). This variant has been reported in al least one individual undergoing multi-gene hereditary cancer panel testing (Table S1, Sutcliffe et al 2020. PubMed ID: 32805687). IT has been reported in an individual with breast cancer (Table S1, Hauke et al. 2018. PubMed ID: 29522266). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/642154/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

Variant summary: The CHEK2 c.1417_1428delGCACGTTTTACG (p.Ala473_Thr476del) variant involves the in-frame deletion of four amino acids located in the protein-kinase domain. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 113468 control chromosomes. One reputable clinical lab has classified the variant as a VUS, while another has classified it as likely pathogenic due to functional data showing a missense variant affecting amino acid 476 to result in abolished kinase activity (Desrichard_2012) and impairment of CHEK2-mediated response to DNA damage (Roeb_2012). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a VUS - possibly pathogenic variant.

Comment:

This variant, c.1417_1428del, results in the deletion of 4 amino acid(s) of the CHEK2 protein (p.Ala473_Thr476del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 231879). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 c.1417_1428del12 variant (also known as p.A473_T476del) is located in coding exon 12 of the CHEK2 gene. This variant results from an in-frame GCACGTTTTACG deletion at nucleotide positions 1417 to 1428. This results in the in-frame deletion of 4 amino acids starting at codon 473. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). These amino acid positions are not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

In-frame deletion of 4 of amino acidsin a non-repeat region predicted to critically alter the protein; Published functional studies assessing missense variants within the deleted region (p.Arg474Cys, p.Arg474His, and p.Thr476Met) demonstrate reduced or absent protein function, suggesting that loss of these residues is damaging (PMID: 22114986, 22419737, 27900359, 30851065, 31050813); Observed in individuals with personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (PMID: 29522266); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22114986, 22419737, 27900359, 30851065, 31050813, 19782031, 32805687, 29522266)

Comment:

The CHEK2 c.1417_1428del12 variant is predicted to result in an in-frame deletion (p.Ala473_Thr476del). This variant may be alternatively referred to as NM_001005735.2:c.1546_1557del (p.Ala516_Thr519del). This variant has been reported in al least one individual undergoing multi-gene hereditary cancer panel testing (Table S1, Sutcliffe et al 2020. PubMed ID: 32805687). IT has been reported in an individual with breast cancer (Table S1, Hauke et al. 2018. PubMed ID: 29522266). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/642154/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.	Hauke J	Cancer medicine	2018	PMID: 29522266

Text-mined citations for rs876659422 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_007194.4(CHEK2):c.1417_1428del (p.Ala473_Thr476del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs876659422 ...