NM_007194.4(CHEK2):c.480_483dup (p.Asp162fs) AND Familial cancer of breast

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 26, 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:: RCV000206009.9

Allele description [Variation Report for NM_007194.4(CHEK2):c.480_483dup (p.Asp162fs)]

NM_007194.4(CHEK2):c.480_483dup (p.Asp162fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.480_483dup (p.Asp162fs)

HGVS:

NC_000022.11:g.28725086_28725089dup
NG_008150.2:g.21778_21781dup
NM_001005735.2:c.609_612dup
NM_001257387.2:c.-298_-295dup
NM_001349956.2:c.444+154_444+157dup
NM_007194.4:c.480_483dupMANE SELECT
NM_145862.2:c.480_483dup
NP_001005735.1:p.Asp205fs
NP_009125.1:p.Asp162fs
NP_665861.1:p.Asp162fs
LRG_302t1:c.480_483dup
LRG_302:g.21778_21781dup
LRG_302p1:p.Asp162fs
NC_000022.10:g.29121073_29121074insTTCT
NC_000022.10:g.29121074_29121077dup
NG_008150.1:g.21746_21749dup
NM_007194.3:c.480_483dupAGAA

Protein change:

D162fs

Links:

dbSNP: rs864622453

NCBI 1000 Genomes Browser:

rs864622453

Molecular consequence:

NM_001257387.2:c.-298_-295dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.609_612dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_007194.4:c.480_483dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_145862.2:c.480_483dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001349956.2:c.444+154_444+157dup - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000260702	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 19, 2015)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21876083, 24713400, 28492532
SCV004045257	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jun 26, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000260702

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 19, 2015)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004045257

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(Jun 26, 2023)

unknown

clinical testing

Citation Link

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

Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer.

Cybulski C, Wokołorczyk D, Jakubowska A, Huzarski T, Byrski T, Gronwald J, Masojć B, Deebniak T, Górski B, Blecharz P, Narod SA, Lubiński J.

J Clin Oncol. 2011 Oct 1;29(28):3747-52. doi: 10.1200/JCO.2010.34.0778. Epub 2011 Aug 29.

PubMed [citation]

PMID:: 21876083

A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland.

Bąk A, Janiszewska H, Junkiert-Czarnecka A, Heise M, Pilarska-Deltow M, Laskowski R, Pasińska M, Haus O.

Hered Cancer Clin Pract. 2014 Apr 8;12(1):10. doi: 10.1186/1897-4287-12-10.

PubMed [citation]

PMID:: 24713400
PMCID:: PMC3991918

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000260702.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This sequence change inserts 4 nucleotide in exon 4 of the CHEK2 mRNA (c.480_483dupAGAA), causing a frameshift at codon 162. This creates a premature translational stop signal (p.Asp162Argfs*25) and is expected to result in an absent or disrupted protein product.

#	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., SCV004045257.2

#	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 pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

#	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: May 1, 2024

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