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

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Feb 2, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001192409.4

Allele description

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 breast ovarian cancer syndrome
Synonyms:
Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001360504Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Feb 2, 2019) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

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

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 (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360504.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: CHEK2 c.917G>C (p.Gly306Ala) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 284924 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (4.6e-05 vs 0.00031). c.917G>C has been reported in the literature in multiple individuals affected with Breast Cancer (Lu_2018, Lolas Hamameh_2017, Susswein_2016, Roeb_2012). These data indicate that the variant is likely to be associated with disease. A co-occurrence with another pathogenic variant has been reported in one case (ATM c.2897_2899delTTCinsGCCAA, p.Val966GlyfsX6); the authors of the study classified the variant of interest as likely pathogenic (Susswein_2016). Experimental evidence evaluating an impact on protein function demonstrated the variant to cause loss of CHEK2-mediated response to DNA damage (Roeb_2012). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (4x) and twice as uncertain significance. Based on the evidence outlined above, until the functional impact of this variant is unequivocally established and additional clinical correlations are ascertained the variant was classified as likely pathogenic

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

Last Updated: Sep 16, 2024