ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.917G>C (p.Gly306Ala) (rs587780192)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116033 SCV000183921 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Structural Evidence
Color RCV000116033 SCV000689747 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000212440 SCV000149942 likely pathogenic not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.917G>C at the cDNA level, p.Gly306Ala (G306A) at the protein level, and results in the change of a Glycine to an Alanine (GGG>GCG). This variant was observed in individuals with familial breast cancer and was shown to cause loss of DNA damage response activity in a yeast-based assay (Le Calvez-Kelm 2011, Roeb 2012). CHEK2 Gly306Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider CHEK2 Gly306Ala to be a likely pathogenic variant.
Invitae RCV000228767 SCV000289716 uncertain significance Familial cancer of breast 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 306 of the CHEK2 protein (p.Gly306Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs587780192, ExAC 0.01%). This variant has been reported in individuals with a personal and/or family history of breast cancer (PMID: 22419737, 21244692, 26681312, 27751358, 28580595). This variant is also known as c.1046G>C , p.Gly349Ala  in the literature. ClinVar contains an entry for this variant (Variation ID: 128089). An experimental study has shown that this missense change disrupts the CHEK2 DNA damage response activity in a yeast-based assay (PMID: 22419737). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000228767 SCV000839474 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000116033 SCV000787998 likely pathogenic Hereditary cancer-predisposing syndrome 2017-08-01 no assertion criteria provided clinical testing

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