ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.592+3A>T (rs587782849)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132447 SCV000187541 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000132447 SCV000537545 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Counsyl RCV000228472 SCV000488829 uncertain significance Familial cancer of breast 2016-06-27 criteria provided, single submitter clinical testing
GeneDx RCV000656830 SCV000210967 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.592+3A>T or IVS4+3A>T and consists of an A>T nucleotide substitution at the +3 position of intron 4 of the CHEK2 gene. This variant, also denoted CHEK2 721+3A>T or IVS3+3A>T using alternate nomenclature, has been observed in an individual with breast cancer and an individual with a MMR-proficient colorectal tumor (Kraus 2017, Pearlman 2017). Multiple in silico models predict this variant to damage or destroy the nearby natural splice donor site, and an RT-PCR study of RNA from an individual with breast cancer suggested that this variant resulted in alternate transcripts that lack exon 4 or exons 4 and 5 (Kraus 2017). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). The adenine (A) nucleotide that is altered is not conserved. In light of only one study to date suggesting that this variant results in a splicing defect, based on the currently available evidence, it is unclear whether CHEK2 c.592+3A>T is pathogenic or benign. We consider it to be a variant of uncertain significance.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000228472 SCV000746463 likely pathogenic Familial cancer of breast 2017-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000290615 SCV000437719 uncertain significance Colorectal cancer 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000348008 SCV000437720 uncertain significance Neoplasm of the breast 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000228472 SCV000289693 uncertain significance Familial cancer of breast 2018-06-05 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587782849, ExAC 0.006%). This variant has been reported in an individual affected with breast cancer (PMID: 27616075) and an individual affected with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 142956). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). An experimental study using patient's blood mRNA showed that this variant results in shortened transcripts due to exon 4 and exons 4+5 skipping, likely resulting in truncated CHEK2 protein products. 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 RCV000228472 SCV000839484 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212430 SCV000601175 uncertain significance not specified 2016-09-08 criteria provided, single submitter clinical testing

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