NM_007194.4(CHEK2):c.917G>C (p.Gly306Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Nov 21, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000116033.29

Allele description [Variation Report for NM_007194.4(CHEK2):c.917G>C (p.Gly306Ala)]

NM_007194.4(CHEK2):c.917G>C (p.Gly306Ala)

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.917G>C (p.Gly306Ala)

Other names:

p.G306A:GGG>GCG

HGVS:

NC_000022.11:g.28699929C>G
NG_008150.2:g.46938G>C
NM_001005735.2:c.1046G>C
NM_001257387.2:c.254G>C
NM_001349956.2:c.716G>C
NM_007194.4:c.917G>CMANE SELECT
NM_145862.2:c.917G>C
NP_001005735.1:p.Gly349Ala
NP_001244316.1:p.Gly85Ala
NP_001336885.1:p.Gly239Ala
NP_009125.1:p.Gly306Ala
NP_665861.1:p.Gly306Ala
LRG_302t1:c.917G>C
LRG_302:g.46938G>C
LRG_302p1:p.Gly306Ala
NC_000022.10:g.29095917C>G
NG_008150.1:g.46906G>C
NM_001005735.1:c.1046G>C
NM_007194.3:c.917G>C
p.G306A

Protein change:

G239A

Links:

dbSNP: rs587780192

NCBI 1000 Genomes Browser:

rs587780192

Molecular consequence:

NM_001005735.2:c.1046G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.254G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.716G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.917G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.917G>C - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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MULTISPECIES: YmjA family protein [Bacteria]
MULTISPECIES: YmjA family protein [Bacteria]
gi|490284235|ref|WP_004180069.1|

Protein
Fistularia commersonii voucher EIL060506 D-loop, partial sequence; mitochondrial
Fistularia commersonii voucher EIL060506 D-loop, partial sequence; mitochondrial
gi|756766354|gb|KP053057.1|

Nucleotide
phosphatidylinositol 4-kinase beta isoform X1 [Homo sapiens]
phosphatidylinositol 4-kinase beta isoform X1 [Homo sapiens]
gi|767909543|ref|XP_011507936.1|

Protein
U5 small nuclear ribonucleoprotein TSSC4 isoform X1 [Danio rerio]
U5 small nuclear ribonucleoprotein TSSC4 isoform X1 [Danio rerio]
gi|528485143|ref|XP_005168945.1|

Protein
RecName: Full=Conotoxin LeD51; Flags: Precursor
RecName: Full=Conotoxin LeD51; Flags: Precursor
gi|122011887|sp|Q3YEF7.1|O2651_CONL

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000183921	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 28, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 16794575, 21244692, 22419737, 26681312, 27751358, 28580595, 30322717, 30851065, 31118792, 32068069, 32658311, 33471991, 37449874 Citation Link,
SCV000689747	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 21, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 21244692, 22419737, 26681312, 26822949, 28486781, 28580595, 30128536, 30303537, 30851065, 31050813, 32068069, 33471991, 34606182, 36521553, 37239058, 37449874, 25741868
SCV000787998	True Health Diagnostics	no assertion criteria provided	Likely pathogenic (Aug 1, 2017)	germline	clinical testing
SCV002537654	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Jun 12, 2021)	germline	curation	PubMed (11) [See all records that cite these PMIDs] 30303537, 30128536, 31050813, 28580595, 28486781, 26681312, 21244692, 31118792, 33050356, 30851065, 22419737 Citation Link

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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, curation

Citations

PubMed

Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange.

Oliver AW, Paul A, Boxall KJ, Barrie SE, Aherne GW, Garrett MD, Mittnacht S, Pearl LH.

EMBO J. 2006 Jul 12;25(13):3179-90. Epub 2006 Jun 22.

PubMed [citation]

PMID:: 16794575
PMCID:: PMC1500991

Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers.

Leedom TP, LaDuca H, McFarland R, Li S, Dolinsky JS, Chao EC.

Cancer Genet. 2016 Sep;209(9):403-407. doi: 10.1016/j.cancergen.2016.08.005. Epub 2016 Aug 15.

PubMed [citation]

PMID:: 27751358

See all PubMed Citations (23)

Details of each submission

From Ambry Genetics, SCV000183921.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The p.G306A variant (also known as c.917G>C), located in coding exon 8 of the CHEK2 gene, results from a G to C substitution at nucleotide position 917. The glycine at codon 306 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in cohorts of breast, ovarian and colorectal cancer patients (Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488; Girard E et al. Int. J. Cancer 2019 04;144(8):1962-1974; Gong R et al. Cancer Manag Res. 2019 Apr;11:3721-3739; Kwong A et al. J Mol Diagn. 2020 04;22:544-554; Akcay IM et al. Int J Cancer. 2021 01;148:285-295). However, this variant has also been reported in healthy controls, including one large case-control study in which this alteration was reported in 3/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). Functional studies for this variant have reported conflicting results. This alteration was reported to result in complete loss of DNA damage response in vivo (Roeb W et al. Hum. Mol. Genet. 2012 Jun; 21(12):2738-44), but behaved as functional in a second in vivo, yeast-based assay (Delimitsou A et al. Hum Mutat. 2019 05;40:631-648). A complementation assay quantifying KAP1-S473 phosphorylation in nontransformed human RPE1 cells showed that p.G306A resulted in 16% function compared to wild-type (Kleiblova P et al. Int. J. Cancer 2019 10;145(7):1782-1797). However, a more recent publication of studies in RPE1-CHEK2-knockout cells reported this alteration as having an "intermediate" impact on protein function (Stolarova L et al. Clin Cancer Res. 2023 Jul:OF1-OF14). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting 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, SCV000689747.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

This missense variant replaces glycine with alanine at codon 306 of the CHEK2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). The mutant protein has been reported to be non-functional in a yeast complementation assay and in a study that measured kinase activities in a human cell line and in a cell-free kinase assay (PMID: 22419737, 31050813) and has been reported to have intermediate impact on KAP1 and CHK2 phosphorylation in a human cell complementation assay (PMID: 37449874). However, this variant has been shown to have neutral impact on DNA damage response in a similar yeast complementation assay system (PMID: 30851065). This variant has been reported in multiple individuals affected with breast cancer (PMID: 21244692, 26681312, 26822949, 28486781, 28580595, 30128536, 30303537, 31050813, 32068069, 34606182, 36521553, 37239058) as well as in unaffected individuals (PMID: 31050813).This variant has been reported in two large breast cancer case-control meta-analyses, observed in 3/60466 cases and 5/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000190) and 8/73048 cases and 7/88658 unaffected controls (PMID: 37449874). This variant has been identified in 12/282524 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and lack of clear disease association, the role of this variant in disease cannot be determined 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

From True Health Diagnostics, SCV000787998.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002537654.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (11)

#	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 26, 2024

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