NM_007194.4(CHEK2):c.1596del (p.Thr533fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 21, 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:: RCV000129505.12

Allele description [Variation Report for NM_007194.4(CHEK2):c.1596del (p.Thr533fs)]

NM_007194.4(CHEK2):c.1596del (p.Thr533fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.1596del (p.Thr533fs)

HGVS:

NC_000022.11:g.28687934del
NG_008150.2:g.58934del
NM_001005735.2:c.1725del
NM_001257387.2:c.933del
NM_001349956.2:c.1395del
NM_007194.4:c.1596delMANE SELECT
NM_145862.2:c.1509del
NP_001005735.1:p.Thr576fs
NP_001244316.1:p.Thr312fs
NP_001336885.1:p.Thr466fs
NP_009125.1:p.Thr533fs
NP_665861.1:p.Thr504fs
LRG_302t1:c.1596del
LRG_302:g.58934del
LRG_302p1:p.Thr533fs
NC_000022.10:g.29083921del
NC_000022.10:g.29083922del
NG_008150.1:g.58902del
NM_007194.3:c.1596del
NM_007194.3:c.1596delC
NM_007194.4:c.1596delCMANE SELECT
p.T533Qfs*33
p.T533QfsX33

Protein change:

T312fs

Links:

dbSNP: rs587781519

NCBI 1000 Genomes Browser:

rs587781519

Molecular consequence:

NM_001005735.2:c.1725del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001257387.2:c.933del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001349956.2:c.1395del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_007194.4:c.1596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_145862.2:c.1509del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000184277	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001343030	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30303537, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184277

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 21, 2023)

germline

clinical testing

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

Citation Link,

SCV001343030

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 3, 2022)

germline

clinical testing

PubMed (2)
[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

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.

Girard E, Eon-Marchais S, Olaso R, Renault AL, Damiola F, Dondon MG, Barjhoux L, Goidin D, Meyer V, Le Gal D, Beauvallet J, Mebirouk N, Lonjou C, Coignard J, Marcou M, Cavaciuti E, Baulard C, Bihoreau MT, Cohen-Haguenauer O, Leroux D, Penet C, Fert-Ferrer S, et al.

Int J Cancer. 2019 Apr 15;144(8):1962-1974. doi: 10.1002/ijc.31921. Epub 2018 Nov 13.

PubMed [citation]

PMID:: 30303537
PMCID:: PMC6587727

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000184277.9

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

Description

The c.1596delC variant, located in coding exon 14 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1596, causing a translational frameshift with a predicted alternate stop codon (p.T533Qfs*33). This alteration was identified in 2/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This deletion and subsequent frameshift occur near the 3' terminus of CHEK2 and result in removal of the last 11 amino acids of CHK2 and insertion of 32 amino acids to the C-terminus, resulting in the elongation of the protein by 21 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV001343030.3

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

Description

This variant deletes 1 nucleotide in exon 15 of the CHEK2 gene, creating a frameshift at codon 533, replacing the last 11 amino acids and extends the length of the encoded protein by 21 amino acids. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial breast cancer who lack pathogenic variants in the BRCA1 or BRCA2 gene (PMID: 30303537) and in an individual with early-onset breast cancer (Color data). This variant has been identified in 3/265102 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.

#	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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