NM_007194.3(CHEK2):c.1567delC (p.Arg523Valfs) AND Familial cancer of breast

Clinical significance:Uncertain significance (Last evaluated: Oct 3, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000205272.2

Allele description

NM_007194.3(CHEK2):c.1567delC (p.Arg523Valfs)

Gene:
CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
22q12.1
Genomic location:
Preferred name:
NM_007194.3(CHEK2):c.1567delC (p.Arg523Valfs)
HGVS:
  • NC_000022.11:g.28687962delG
  • NG_008150.1:g.58873delC
  • NM_007194.3:c.1567delC
  • NP_009125.1:p.Arg523Valfs
  • NC_000022.10:g.29083950delG
  • p.R523Vfs*43
  • p.R523VfsX43
Links:
dbSNP: rs587782684
NCBI 1000 Genomes Browser:
rs587782684
Allele Frequency:
0.00003(-)
Molecular consequence:
  • NM_007194.3:c.1567delC - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Familial cancer of breast
Synonyms:
CHEK2-Related Breast Cancer
Identifiers:
MedGen: C0346153; OMIM: 114480

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000260804Invitaecriteria provided, single submitter
Uncertain significance
(Oct 3, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Invitae, SCV000260804.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This sequence change deletes 1 nucleotide in exon 15 of the CHEK2 mRNA (c.1567delC), causing a frameshift at codon 523. This extends the open reading frame of CHEK2 by 21 amino acids beyond the translation stop codon in the last exon (p.Arg523Valfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a disrupted CHEK2 protein by creating 42 random amino acid residues at the end of the protein. While this variant is present in population databases (rs587782684), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 142737). The last exon of the CHEK2 gene contains coding sequences for a nuclear localization signal (NLS, residues 515-522), which is necessary for CHEK2 cellular functioning in the nucleus (PMID: 12909615, 18004398). This variant causes a frameshift at codon 523 and is not expected to affect the NLS, but it may affect protein structure and/or stability. Functional studies have not been done to test its effect on protein function. In summary, this is a rare frameshift variant that is not expected to directly affect the known NLS domain of the CHEK2 protein, but its impact on protein function is uncertain. It has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 3, 2018