ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1461+1G>A (rs886039629)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569979 SCV000669232 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-24 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
GeneDx RCV000255259 SCV000322553 likely pathogenic not provided 2016-04-11 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1461+1G>A or IVS13+1G>A and consists of a G>A nucleotidesubstitution at the +1 position of intron 13 of the CHEK2 gene. This variant destroys a canonical splice donor site andis 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 not, to our knowledge, been published inthe literature as a germline variant; however it has been reported as a somatic variant in esophageal cancer (Zhang2015). Based on the currently available information, we consider CHEK2 c.1461+1G>A to be a likely pathogenicvariant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000468702 SCV000839937 pathogenic Familial cancer of breast 2017-03-07 criteria provided, single submitter clinical testing This c.1461+1G>A variant 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 patient was not available (SCV000322553.3). This variant affects the invariant donor splice site of intron 13 of the CHEK2 gene. Whole not validated for clinical use, computer-based algorithms predict this c.1461+1G>A change to disrupt this splicing site. A c.1461 +2T>C affecting the same invariant splice site was reported in a cohort of patients with breast and/or ovarian cancer [PMID 24549055]. This variant is classified as pathogenic.
Invitae RCV000468702 SCV000550445 likely pathogenic Familial cancer of breast 2016-12-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with a CHEK2-related disease. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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