ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.793-1G>A (rs730881687)

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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 RCV000214915 SCV000273338 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Color RCV000214915 SCV000537628 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Counsyl RCV000464029 SCV000785943 likely pathogenic Familial cancer of breast 2018-01-17 criteria provided, single submitter clinical testing
GeneDx RCV000160429 SCV000210975 likely pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.793-1G>A or IVS6-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 6 of the CHEK2 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in individuals with breast cancer, at least one individual with prostate cancer, and in other individuals undergoing multi-gene panel testing (Schrader 2015, Leedom 2016, Susswein 2016, Wu 2018). Based on the currently available information, we consider CHEK2 c.793-1G>A to be a likely pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000464029 SCV000839943 pathogenic Familial cancer of breast 2017-06-02 criteria provided, single submitter clinical testing This c.793-1G>A variant in the CHEK2 gene has not been observed in our cohort database nor has been detected in the ExAC database. This variant was however reported in ClinVar but the clinical presentation of the patients was not available (SCV000210975.9, SCV000273338.2). This variant affect the invariant acceptor splice site of intron 6 of the CHEK2 gene. While not clinically validated, computer-based algorithms predict this c.793-1G>A change to affect splicing by creating an alternative splice site 1bp downstream and thus creating a frameshift. This variant is classified as pathogenic.
Invitae RCV000464029 SCV000550453 pathogenic Familial cancer of breast 2018-12-28 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 26681312), and in individuals who underwent genetic tests for the risk of hereditary cancer (PMID: 27751358). It has also been observed to segregate with CHEK2-related cancers in affected families (Invitae). ClinVar contains an entry for this variant (Variation ID: 182430). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.

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