NM_007194.4(CHEK2):c.480A>G (p.Ile160Met) AND not provided

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Aug 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:: RCV000586231.20

Allele description [Variation Report for NM_007194.4(CHEK2):c.480A>G (p.Ile160Met)]

NM_007194.4(CHEK2):c.480A>G (p.Ile160Met)

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.480A>G (p.Ile160Met)

Other names:

p.I160M:ATA>ATG

HGVS:

NC_000022.11:g.28725089T>C
NG_008150.2:g.21778A>G
NM_001005735.2:c.609A>G
NM_001257387.2:c.-298A>G
NM_001349956.2:c.444+154A>G
NM_007194.4:c.480A>GMANE SELECT
NM_145862.2:c.480A>G
NP_001005735.1:p.Ile203Met
NP_009125.1:p.Ile160Met
NP_665861.1:p.Ile160Met
LRG_302t1:c.480A>G
LRG_302:g.21778A>G
LRG_302p1:p.Ile160Met
NC_000022.10:g.29121077T>C
NG_008150.1:g.21746A>G
NM_001005735.2:c.609A>G
NM_007194.3:c.480A>G
p.I160M

Protein change:

I160M

Links:

dbSNP: rs575910805

NCBI 1000 Genomes Browser:

rs575910805

Molecular consequence:

NM_001257387.2:c.-298A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001349956.2:c.444+154A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001005735.2:c.609A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.480A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.480A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149929	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Aug 2, 2023)	germline	clinical testing	Citation Link,
SCV001134170	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Mar 10, 2021)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15095295, 22419737, 25629968, 30851065, 28779002, 25186627, 26467025
SCV001549344	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV002036907	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV002037302	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV002038283	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing

Help

Summary from all submissions

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

Citations

PubMed

Limited relevance of the CHEK2 gene in hereditary breast cancer.

Dufault MR, Betz B, Wappenschmidt B, Hofmann W, Bandick K, Golla A, Pietschmann A, Nestle-Krämling C, Rhiem K, Hüttner C, von Lindern C, Dall P, Kiechle M, Untch M, Jonat W, Meindl A, Scherneck S, Niederacher D, Schmutzler RK, Arnold N.

Int J Cancer. 2004 Jun 20;110(3):320-5.

PubMed [citation]

PMID:: 15095295

Response to DNA damage of CHEK2 missense mutations in familial breast cancer.

Roeb W, Higgins J, King MC.

Hum Mol Genet. 2012 Jun 15;21(12):2738-44. doi: 10.1093/hmg/dds101. Epub 2012 Mar 13.

PubMed [citation]

PMID:: 22419737
PMCID:: PMC3363333

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000149929.20

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

Description

Published functional studies are inconclusive: partial to no impact on response to DNA damage and growth rate, expression levels similar to wild type, and phosphorylation of Thr68 when irradiated similar to wild type (Roeb et al., 2012; Delimitsou et al., 2019; Wagener et al., 2022); Observed in individuals with breast cancer (Dufault et al., 2004; Mohamad et al., 2015; Tsai et al., 2019; Akcay et al., 2020; da Costa e Silva Carvalho et al., 2020; Moradian et al., 2021; Andrikopoulou et al., 2022; Zografos et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.609A>G or p.Ile203Met; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22419737, 15095295, 25629968, 28553140, 30303537, 32546565, 27153395, 30851065, 31159747, 31296309, 30374176, 32039725, 32900738, 33558524, 32658311, 33471991, 35127508, 28779002, 35772246, 36468172, 25186627, 19782031, 36011273)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134170.4

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

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001549344.1

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

Description

The CHEK2 p.Ile160Met variant was identified in 4 of 2906 proband chromosomes (frequency: 0.001) from German and Malaysian individuals or families with BRCA1/2 negative HBOC or breast cancer and was identified in 1 of 1540 control chromosomes (freq: 0.001) from healthy individuals (Dufault 2004, Mohamad 2015). Functional analyses using a yeast based assay to assess in vivo CHEK2 mediated response to DNA damage showed the variant had a partial response to DNA damage (Roeb 2012). In this study, the variant co-occurred with CHEK2 p.G167R which was found to have no response to DNA damage; further, segregation studies showed the p.Ile160Met was carried by the affected father diagnosed with breast cancer and his elderly unaffected sister. The variant was also identified in the following databases: dbSNP (ID: rs575910805) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: uncertain significance by GeneDx and Ambry Genetics, and likely benign by Invitae), Clinvitae (3x), Cosmic (1x in a Ewings sarcoma tumour), and was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 31 of 277194 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). Observations by population include, European Non-Finnish in 7 of 126678 chromosomes (freq. 0.00006) and South Asian in 24 of 30782 chromosomes (freq. 0.0008); it was not seen in the East Asian, Other, Latino, Ashkenazi Jewish, and European Finnish populations. The p.Ile160 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of Met to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. 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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036907.1

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

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV002037302.1

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

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV002038283.1

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

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

Last Updated: Mar 16, 2024

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