NM_007194.4(CHEK2):c.917G>C (p.Gly306Ala) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Aug 18, 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:: RCV000212440.19

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]

Observations:

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
SCV000149942	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Aug 18, 2023)	germline	clinical testing	Citation Link,
SCV002022541	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 9, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002503259	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 1, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22419737, 30322717, 30851065, 30303537, 31050813, 28580595, 25741868
SCV002774275	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Jun 1, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 33471991, 33050356, 31118792, 32860008, 32068069, 32658311, 22419737, 26681312, 27751358, 28580595, 31050813, 30851065, 30303537, 30128536, 28486781, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
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

Germline pathogenic variants identified in women with ovarian tumors.

Carter NJ, Marshall ML, Susswein LR, Zorn KK, Hiraki S, Arvai KJ, Torene RI, McGill AK, Yackowski L, Murphy PD, Xu Z, Solomon BD, Klein RT, Hruska KS.

Gynecol Oncol. 2018 Dec;151(3):481-488. doi: 10.1016/j.ygyno.2018.09.030. Epub 2018 Oct 12.

PubMed [citation]

PMID:: 30322717

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

See all PubMed Citations (18)

Details of each submission

From GeneDx, SCV000149942.18

#	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 demonstrate at least an intermediate impact on kinase activity in human cell-based assays and mixed results in yeast studies (Roeb et al., 2012; Delimitsou et al., 2019; Kleiblova et al., 2019; Stolarova et al., 2023); Observed in individuals with early-onset and/or familial breast cancer and/or colorectal cancer (Le Calvez-Kelm et al., 2011; Roeb et al., 2012; Tung et al., 2015; Lolas Hamameh et al., 2017; Xie et al., 2018; Girard et al., 2019; Akcay et al., 2020; Kwong et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37239058, 30128536, 32805687, 30322717, 31118792, 21244692, 26787654, 26681312, 27751358, 28580595, 28301460, 25186627, 28486781, 30851065, 31050813, 30303537, 32068069, 32860008, 33050356, 32658311, 29922827, 33471991, 35264596, 37449874, 16794575, 22419737, 19782031, 36521553)

#	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 Revvity Omics, Revvity, SCV002022541.3

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

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002503259.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002774275.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The CHEK2 c.917G>C (p.Gly306Ala) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 26681312 (2015), 27751358 (2016), 28486781 (2017), 28580595 (2018), 30128536 (2018), 30303537 (2019), 32068069 (2020), 32658311 (2021)), ovarian cancer (PMID: 30322717 (2018)), melanoma (PMID: 33050356 (2020)), and colorectal cancer (PMID: 31118792 (2019)). Functional studies using yeast-based assays have produced conflicting results (PMIDs: 30851065 (2019), 22419737 (2012)), but a functional study utilizing human cells suggested this variant is damaging (PMID: 31050813 (2019)). The frequency of this variant in the general population, 0.00015 (3/19946 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

#	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: Aug 25, 2024

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