ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1096-4T>C (rs587782840)

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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 RCV000132429 SCV000187522 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000590391 SCV000329283 uncertain significance not provided 2017-11-01 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1096-4T>C or IVS10-4T>C and consists of a T>C nucleotide substitution at the -4 position of intron 10 of the CHEK2 gene. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. While one in silico model predicts this variant to cause an insignificant decrease in use of the natural splice acceptor site, two others are uninformative; therefore, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). The thymine (T) nucleotide that is altered is conserved through mammals. Based on currently available information, it is unclear whether CHEK2 c.1096-4T>C is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000412166 SCV000488624 uncertain significance Familial cancer of breast 2016-05-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590391 SCV000698760 uncertain significance not provided 2016-03-01 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide located in an intronic position not widely known to affect splicing. Mutation taster predicts disease causing outcome for this substitution while 5/5 in silico tools via Alamut predict the variant not to have an effect on splicing. The variant was found in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.0046% which exceeds the maximal expected allele frequency of a disease causing CHEK2 allele (0.0028%) indicating neutrality. To our knowledge, the variant was not reported in affected individuals and in vitro/vivo studies assessing the impact of the variant on slicing were not published at the time of scoring either. A clinical laboratory classifies variant as Uncertain" (without evidence to independently evaluate). Considering all evidence, the variant was classified as a VUS-possibly benign until more information becomes available.
Invitae RCV000590391 SCV000757402 likely benign not provided 2019-02-04 criteria provided, single submitter clinical testing
Color RCV000132429 SCV000903060 likely benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing

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