ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1254_1255insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNACCTCGTGATCCGCCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCCAGGAGTTATTCTTTTT (p.Ile419delinsPhePhePhePhePhePheXaaXaaXaaXaaThrSerTer)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003607853 SCV004412308 pathogenic Familial cancer of breast 2022-11-04 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 11 of the CHEK2 gene (c.1254_1255ins?), causing a frameshift at codon 419 (p.Ile419fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product.

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