NM_007194.4(CHEK2):c.319+2T>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 2, 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:: RCV000131434.24

Allele description [Variation Report for NM_007194.4(CHEK2):c.319+2T>A]

NM_007194.4(CHEK2):c.319+2T>A

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.319+2T>A

HGVS:

NC_000022.11:g.28734401A>T
NG_008150.2:g.12466T>A
NM_001005735.2:c.319+2T>A
NM_001257387.2:c.-459+2T>A
NM_001349956.2:c.319+2T>A
NM_007194.4:c.319+2T>AMANE SELECT
NM_145862.2:c.319+2T>A
LRG_302t1:c.319+2T>A
LRG_302:g.12466T>A
NC_000022.10:g.29130389A>T
NM_001005735.1:c.319+2T>A
NM_007194.3:c.319+2T>A

Links:

dbSNP: rs587782401

NCBI 1000 Genomes Browser:

rs587782401

Molecular consequence:

NM_001005735.2:c.319+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001257387.2:c.-459+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001349956.2:c.319+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_007194.4:c.319+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_145862.2:c.319+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186416	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23960188, 28608266 Citation Link,
SCV000684628	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 21, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 26681312, 27696107, 28608266, 30333958, 30927251, 31882575, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186416

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 2, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000684628

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 21, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Citations

PubMed

DNA repair genes are selectively mutated in diffuse large B cell lymphomas.

de Miranda NF, Peng R, Georgiou K, Wu C, Falk Sörqvist E, Berglund M, Chen L, Gao Z, Lagerstedt K, Lisboa S, Roos F, van Wezel T, Teixeira MR, Rosenquist R, Sundström C, Enblad G, Nilsson M, Zeng Y, Kipling D, Pan-Hammarström Q.

J Exp Med. 2013 Aug 26;210(9):1729-42. doi: 10.1084/jem.20122842. Epub 2013 Aug 19.

PubMed [citation]

PMID:: 23960188
PMCID:: PMC3754869

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2. doi: 10.1038/gim.2016.21.

PubMed [citation]

PMID:: 26681312
PMCID:: PMC4985612

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000186416.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.319+2T>A pathogenic intronic mutation results from a T to A substitution two nucleotides after coding exon 1 in the CHEK2 gene. The alteration has previously been reported in an individual diagnosed with a microsatellite-stable colorectal cancer at age 76 years (Rohlin A et al. Fam. Cancer 2017 Apr;16(2):195-203) and in another individual diagnosed with thyroid cancer and bilateral breast cancer who also had a family history of breast, thyroid, and endometrial cancers (Dominguez-Valentin M et al. Fam. Cancer 2018 Jan;17(1):141-153).This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000684628.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant causes a T>A nucleotide substitution at the +2 position of intron 2 of the CHEK2 gene. Computational splicing tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional RNA studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and ovarian cancer (PMID: 26681312, 28608266, 30333958, 31882575) and in an individual who was referred for clinical familial adenomatous polyposis- and/or Lynch syndrome mutation analyses (PMID: 27696107). In the Finnish population where this variant has been identified in 15/25102 chromosomes, this variant is associated with elevated risk of breast cancer (PMID: 30927251). This variant has been identified in 29/282228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Likely Pathogenic.

#	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

Last Updated: Oct 20, 2024

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