Submissions for variant NM_007194.4(CHEK2):c.444+2T>C

dbSNP: rs560596101

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483398	SCV000572152	pathogenic	not provided	2019-11-08	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge; Also known as c.573+2T>C or IVS2+2T>C
Invitae	RCV000543761	SCV000633188	pathogenic	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422638). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 12533788; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000562639	SCV000661735	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	The c.444+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 2 in the CHEK2 gene. This alteration was identified in a cohort of 2508 individuals who underwent multi-gene hereditary cancer panel testing and were found to have at least one pathogenic or likely pathogenic variant in CHEK2 (Sutcliffe EG et al. Cancer Genet, 2020 08;246-247:12-17). 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 will result in the creation or strengthening of a novel splice donor site; however direct evidence is insufficient at this time. 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.
Fulgent Genetics, Fulgent Genetics	RCV000763474	SCV000894256	pathogenic	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000483398	SCV002019287	pathogenic	not provided	2019-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000543761	SCV004035137	pathogenic	Familial cancer of breast	2023-09-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency).This nucleotide position is highly conserved  ( PhyloP=6.76) . This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422638) classified as pathogenic . Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 12533788). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000543761	SCV004042863	likely pathogenic	Familial cancer of breast	2023-06-23	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	RCV000543761	SCV004217589	likely pathogenic	Familial cancer of breast	2023-08-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000562639	SCV004361398	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 3 of the CHEK2 gene, changing a GT donor site to a GC donor site. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing, potentially utilizing a cryptic GT donor site 4 nucleotides downstream. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. Different variants affecting the same splice donor, c.444+1G>A and c.444+1G>C, c.444+1G>T, c.444+1del are known to be disease-causing (ClinVar variation ID: 928268, 419303, 128075, 126914). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.