NM_007194.4(CHEK2):c.1376-1G>C AND Familial cancer of breast

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Nov 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000456304.11

Allele description [Variation Report for NM_007194.4(CHEK2):c.1376-1G>C]

NM_007194.4(CHEK2):c.1376-1G>C

Gene:

CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.1376-1G>C

HGVS:

NC_000022.11:g.28694118C>G
NG_008150.2:g.52749G>C
NM_001005735.2:c.1505-1G>C
NM_001257387.2:c.713-1G>C
NM_001349956.2:c.1175-1G>C
NM_007194.4:c.1376-1G>CMANE SELECT
NM_145862.2:c.1289-1G>C
LRG_302t1:c.1376-1G>C
LRG_302:g.52749G>C
NC_000022.10:g.29090106C>G
NM_007194.3:c.1376-1G>C

Links:

dbSNP: rs876659287

NCBI 1000 Genomes Browser:

rs876659287

Molecular consequence:

NM_001005735.2:c.1505-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001257387.2:c.713-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001349956.2:c.1175-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_007194.4:c.1376-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_145862.2:c.1289-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

Recent activity

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Mus musculus
Mus musculus
FXR cistrome in mouse liver

BioProject
PREDICTED: Chelonia mydas sarcoglycan delta (SGCD), transcript variant X3, mRNA
PREDICTED: Chelonia mydas sarcoglycan delta (SGCD), transcript variant X3, mRNA
gi|2092467839|ref|XM_043553161.1|

Nucleotide
Tbc1d16 TBC1 domain family, member 16 [Mus musculus]
Tbc1d16 TBC1 domain family, member 16 [Mus musculus]
Gene ID:207592

Gene
D11Mit342 AND (alive[prop]) (1)
Gene
Viburnum toronis isolate PWS1799 photosystem Q/B protein (psbA) gene, partial cd...
Viburnum toronis isolate PWS1799 photosystem Q/B protein (psbA) gene, partial cds; and psbA-trnH intergenic spacer, partial sequence; chloroplast
gi|371928895|gb|HQ592103.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000550555	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 22, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 32531112, 16199547, 21876083, 24713400, 28492532
SCV004043345	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jun 28, 2023)	unknown	clinical testing	Citation Link,
SCV005058426	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000550555

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 22, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004043345

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely pathogenic
(Jun 28, 2023)

unknown

clinical testing

Citation Link,

SCV005058426

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 15, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Skin cancer risk in CHEK2 mutation carriers.

Bui AN, LeBoeuf NR, Nambudiri VE.

J Eur Acad Dermatol Venereol. 2021 Feb;35(2):353-359. doi: 10.1111/jdv.16729. Epub 2020 Jul 8. Review.

PubMed [citation]

PMID:: 32531112

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000550555.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 410064). Disruption of this splice site has been observed in individual(s) with skin cancer (PMID: 32531112). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 12 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004043345.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV005058426.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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