NM_007194.4(CHEK2):c.917G>C (p.Gly306Ala) AND Familial cancer of breast

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Mar 29, 2024
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:: RCV000228767.18

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

Recent activity

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recombining binding protein suppressor of hairless isoform X1 [Rattus norvegicus...
recombining binding protein suppressor of hairless isoform X1 [Rattus norvegicus]
gi|2678896453|ref|XP_063129654.1|

Protein
PREDICTED: Rattus norvegicus recombination signal binding protein for immunoglob...
PREDICTED: Rattus norvegicus recombination signal binding protein for immunoglobulin kappa J region (Rbpj), transcript variant X1, mRNA
gi|2678896452|ref|XM_063273584.1|

Nucleotide
ankyrin repeat and EF-hand domain containing 1a [Danio rerio]
ankyrin repeat and EF-hand domain containing 1a [Danio rerio]
gi|70887735|ref|NP_001020714.1|

Protein
multiple C2 and transmembrane domain-containing protein 1 isoform X2 [Danio reri...
multiple C2 and transmembrane domain-containing protein 1 isoform X2 [Danio rerio]
gi|2800590037|ref|XP_068077619.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000289716	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 30, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 21244692, 26681312, 27751358, 28486781, 28580595, 30128536, 30303537, 30322717, 22419737, 30851065, 31050813, 28492532
SCV000839474	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004217480	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 29, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000289716

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 30, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000839474

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(Jul 2, 2018)

unknown

clinical testing

Citation Link,

SCV004217480

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 29, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	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

Citations

PubMed

Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study.

Le Calvez-Kelm F, Lesueur F, Damiola F, Vallée M, Voegele C, Babikyan D, Durand G, Forey N, McKay-Chopin S, Robinot N, Nguyen-Dumont T, Thomas A, Byrnes GB; Breast Cancer Family Registry., Hopper JL, Southey MC, Andrulis IL, John EM, Tavtigian SV.

Breast Cancer Res. 2011 Jan 18;13(1):R6. doi: 10.1186/bcr2810.

PubMed [citation]

PMID:: 21244692
PMCID:: PMC3109572

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2. doi: 10.1038/gim.2016.21.

PubMed [citation]

PMID:: 26681312
PMCID:: PMC4985612

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000289716.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 306 of the CHEK2 protein (p.Gly306Ala). This variant is present in population databases (rs587780192, gnomAD 0.02%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 21244692, 22419737, 26681312, 27751358, 28486781, 28580595, 30128536, 30303537, 30322717, 31050813). This variant is also known as c.1046G>C, p.Gly349Ala. ClinVar contains an entry for this variant (Variation ID: 128089). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22419737, 30851065, 31050813). In summary, this variant is a rare missense change that has been observed in affected individuals. However, it is also present in the population, and there is a lack of family segregation and case-control studies in evaluating cancer risk, which are important to determine the disease-causing role of this variant in this lower-penetrance gene. Moreover, experimental studies have reported conflicting results regarding the effect of this variant on CHEK2 protein function. Therefore, it has been 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 Mendelics, SCV000839474.2

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

From Baylor Genetics, SCV004217480.2

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

Last Updated: Oct 26, 2024

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