Submissions for variant NM_007194.4(CHEK2):c.1543-11_1543-2del

dbSNP: rs2145739661

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001728027	SCV001976409	likely pathogenic	Familial cancer of breast	2021-09-22	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003321868	SCV004026255	likely pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	PP5, PM2_SUP, PVS1_STR
Ambry Genetics	RCV003365440	SCV004055686	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing	The c.1543-11_1543-2del10 intronic variant, located in intron 13 of the CHEK2 gene, results from a deletion of 10 nucleotides within intron 13 of the CHEK2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however direct evidence is insufficient (Ambry internal data). The canonical acceptor site is well conserved in available vertebrate species. This alteration occurs in the 3' terminus of the CHEK2 gene, and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the predicted aberrant splicing is unknown; however, the impacted region is critical for protein function and a significant portion of the protein is expected to be affected (Ambry internal data). The alteration is predicted to disrupt the nuclear localization signal of the protein (Zannini L et al. J Biol Chem. 2003 Oct 24;278(43):42346-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.