Submissions for variant NM_007194.4(CHEK2):c.846+1G>A

dbSNP: rs864622149

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492671	SCV000581176	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-09-23	criteria provided, single submitter	clinical testing	The c.846+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of the CHEK2 gene. This alteration was identified in a woman diagnosed with breast cancer at age 55, whose family history includes three first-degree relatives diagnosed with breast cancer under the age of 50 (Slavin TP et al. Front Oncol. 2015 Sep;5:208). This alteration, designated as c.1051+1C>T, was reported in a patient diagnosed with early-onset breast, uterine, and ovarian cancers (Whitworth J et al. Am. J. Hum. Genet. 2018 07;103:3-18). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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.
GeneDx	RCV000522765	SCV000620566	likely pathogenic	not provided	2018-07-06	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.846+1G>A or IVS7+1G>A and consists of a G>A nucleotidesubstitution at the +1 position of intron 7 of the CHEK2 gene. This variant destroys a canonical splice donor site and ispredicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published inthe literature. Based on the currently available information, we consider CHEK2 c.846+1G>A to be a likely pathogenicvariant.
Invitae	RCV000635951	SCV000757379	likely pathogenic	Familial cancer of breast	2023-09-21	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 428910). This variant is also known as c.975+1G>A. Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 26484312, 32805687). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 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).
Academic Department of Medical Genetics, University of Cambridge	RCV000492671	SCV000992229	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Myriad Genetics, Inc.	RCV000635951	SCV004044027	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.