ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.792+2T>C

gnomAD frequency: 0.00001  dbSNP: rs545982789
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205137 SCV000261050 likely pathogenic Familial cancer of breast 2022-01-20 criteria provided, single submitter clinical testing This variant is also known as c.683+2T>C. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 220480). Disruption of this splice site has been observed in individual(s) with CHEK2-related conditions (PMID: 32885271, 32906215). This variant is present in population databases (rs545982789, gnomAD 0.002%). This sequence change affects a donor splice site in intron 6 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Ambry Genetics RCV000570644 SCV000669261 likely pathogenic Hereditary cancer-predisposing syndrome 2023-04-13 criteria provided, single submitter clinical testing The c.792+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 5 in the CHEK2 gene. In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also reported as being found in at least one individual in a cohort of 516 patients being evaluated for suspected hereditary breast and ovarian cancer (Vargas-Parra G et al. Hum Mutat. 2020 12;41(12):2128-2142). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Mendelics RCV000205137 SCV001141360 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000205137 SCV004045156 likely pathogenic Familial cancer of breast 2023-06-27 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics RCV000205137 SCV004217565 uncertain significance Familial cancer of breast 2023-09-07 criteria provided, single submitter clinical testing

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