Submissions for variant NM_007194.4(CHEK2):c.319+1G>A

gnomAD frequency: 0.00001  dbSNP: rs765080766

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573370	SCV000666379	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	The c.319+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the CHEK2 gene. 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV000635773	SCV000757195	likely pathogenic	Familial cancer of breast	2023-09-15	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: 481726). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 2 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).
Color Diagnostics, LLC DBA Color Health	RCV000573370	SCV001350892	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-16	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 2 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although RNA studies have not been reported for this variant, this variant is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250812 chromosomes 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258068	SCV001434900	likely pathogenic	Breast cancer, susceptibility to; Prostate cancer, susceptibility to	2019-10-23	criteria provided, single submitter	clinical testing	The c.319+1G>A variant occurs in the donor splice site of intron 2 of the CHEK2 gene and is predicted to affect splicing, likely resulting in disrupted or absent protein product via nonsense mediated decay. While this particular variant has not been reported in individuals with CHEK2-related cancer, a different variant also at the same donor splice site (c.319+2T>A) is associated with thyroid cancer, breast cancer, and colorectal cancer (PMID: 28608266, 26681312, 27696107). The c.319+1G>A variant is very rare in population databases (2/250812 alleles in gnomAD). Loss-of-function variants in CHEK2 are considered pathogenic (PMID: 21876083, 24713400). This variant has been classified as Likely Pathogenic, however due to low allele fraction detected on NGS in this sample, this could represent somatic mosaicism. The clinical significance of this finding warrants further investigation.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000635773	SCV001499788	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000635773	SCV004043405	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	RCV000635773	SCV004217764	likely pathogenic	Familial cancer of breast	2021-04-01	criteria provided, single submitter	clinical testing