ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1259+5G>A

dbSNP: rs1555913629
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564314 SCV000666363 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-03 criteria provided, single submitter clinical testing The c.1259+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 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 6500 samples (13000 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 200000 alleles tested) in our clinical cohort. This nucleotide position is highly 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 splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001316769 SCV001507404 uncertain significance Familial cancer of breast 2020-03-26 criteria provided, single submitter clinical testing 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 481717). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 11 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein, but it affects a nucleotide within the consensus splice site of the intron.
Color Diagnostics, LLC DBA Color Health RCV000564314 SCV002052676 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-26 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +5 position of intron 11 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. 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). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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