Submissions for variant NM_007194.4(CHEK2):c.444+5G>C

dbSNP: rs189961251

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206019	SCV000260642	uncertain significance	Familial cancer of breast	2015-09-14	criteria provided, single submitter	clinical testing	In summary, this is a novel intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance. Nucleotide substitutions at +5 position of the intron are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing through a loss of splice donor site, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases and has not been reported in the literature. This variant affects a highly conserved nucleotide within the consensus splice site of intron 3. The majority of introns have a G nucleotide at this position (PMID: 9536098).
GeneDx	RCV002460986	SCV002757497	uncertain significance	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.