ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.320-3C>A

dbSNP: rs863224749
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195464 SCV000254938 uncertain significance Familial cancer of breast 2023-11-17 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein. It affects a nucleotide within the consensus splice site. 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: 216645). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000219631 SCV000276980 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-26 criteria provided, single submitter clinical testing The c.320-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 2 in the CHEK2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 72000 alleles tested) in our clinical cohort. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native acceptor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.320-3C>A remains unclear.

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