ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.846+4_846+7del

dbSNP: rs764884641
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197064 SCV000254953 pathogenic Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs764884641, gnomAD 0.005%). This variant has been observed in individual(s) with hereditary breast cancer (hereditary breast cancer). This variant is also known as c.846+4delAGTA. ClinVar contains an entry for this variant (Variation ID: 216652). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of either exon 7 (in-frame) or exons 7-8 (out-of-frame) (PMID: 30264118; Invitae). The resulting mRNA is expected to either preserve the integrity of the reading frame or undergo nonsense-mediated decay. This variant disrupts the serine/threonine kinase domain of the CHEK2 protein, which is essential for protein function (PMID: 30264118, 31843900, 29785007). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000222175 SCV000272956 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-27 criteria provided, single submitter clinical testing The c.846+4_846+7delAGTA intronic variant is located 4 nucleotides after coding exon 6 of the CHEK2 gene and results from a deletion of 4 nucleotides at positions c.846+4 to c.846+7. In one study, c.846+4_846+7delAGTA was detected in a French woman with breast cancer who previously tested negative for mutations in the BRCA1 and BRCA2 genes (Desrichard A et al. Breast Cancer Res. 2011;13:R119). This nucleotide region is well 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; and RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000656831 SCV000329279 likely pathogenic not provided 2021-07-07 criteria provided, single submitter clinical testing Variant affecting the +5 splice site position causing abnormal splicing and resulting in multiple aberrant transcripts that would be predicted to critically alter the protein (Cai 2009, Roeb 2012, Casadei 2019); Published functional studies support a damaging effect: absent kinase activity (Kleiblova 2019); Observed in multiple individuals with breast cancer, segregating with disease in several families, but two families additionally carried pathogenic variants in other breast cancer susceptibility genes (Desrichard 2011, Mersch 2018, Kleiblova 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31843900, 22114986, 27485037, 31050813, 30264118, 27535533, 32906215)
Genetic Services Laboratory,University of Chicago RCV000343110 SCV000594117 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000343110 SCV000601180 uncertain significance not specified 2016-10-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656831 SCV000888125 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000222175 SCV000910787 pathogenic Hereditary cancer-predisposing syndrome 2021-07-26 criteria provided, single submitter clinical testing This variant deletes 4 nucleotides at the +4 to +7 position of intron 7 of the CHEK2 RNA. Functional RNA studies have shown that this variant produces two mutant transcripts (PMID: 31050813, 31843900). One mutant transcript causes an out-of-frame skipping of exons 7 and 8, creating a frameshift and premature translation stop signal and expected to result in an absent or non-functional protein product. The other mutant transcript causes an in-frame skipping of exon 7, creating a partial deletion of the kinase domain. A functional study has shown that a variant lacking exon 7 displays significantly decreased kinase activity (PMID: 31050813). This variant has been reported in more than ten individuals affected with familial breast cancer (PMID: 22114986, 30264118, 31050813; Color internal data). This variant has also been identified in 8/278088 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000656831 SCV001447154 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002229123 SCV002511770 likely pathogenic Hereditary breast ovarian cancer syndrome 2022-04-22 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.846+4_846+7delAGTA is located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to two populations of transcript, one causing the complete in-frame skipping of exon 7 and another leading to an out of frame skipping of exons 7 and 8 (Casadei_2019). The variant allele was found at a frequency of 2.8e-05 in 246676 control chromosomes. c.846+4_846+7delAGTA has been reported in the literature in settings of multigene panel testing and focused CHEK2 screening among individuals with a personal and family history of breast and other cancers (example, Desrichard_2011, Tung_2015, Kleibova_2019, Vargas-Parra_2020, Stolarova_2020, Barbalho_2020) and in at-least once in a cohort of individuals without a cancer diagnosis (example, Kraemer_2019). However, it has also been reported as a VUS in settings of multigene panel testing in an individual with male breast cancer (Tung_2015), as a VUS when classified based on the framework of Senol-Cosar_2019 for low penetrant genes (Vargas-Parra_2020). Several instances of unaffected family members harboring this variant have also been reported (Kleibova_2019). These data indicate that the variant is likely to be associated with disease with a variable penetrance. At-least three instances of co-occurrences with other putative pathogenic variant(s) have been reported (ATM, p.R2034Cfs*; BRCA2, p.N433Qfs*; BRCA2, p.C1200*), providing supporting evidence for a benign/non-actionable role (Kleibova_2019). At least one publication reports experimental evidence evaluating an impact on protein function (Kleibova_2019). The most pronounced variant effect results in a significantly diminished CHEK2 kinase activity in vitro in an experimental system that measured relative levels of CHK2-dependent KAP1-S473 phosphorylation in RPE1-CHEK2-KO cells. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely Pathogenic, n=7; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sema4,Sema4 RCV000222175 SCV002537644 likely pathogenic Hereditary cancer-predisposing syndrome 2022-01-24 criteria provided, single submitter curation
MGZ Medical Genetics Center RCV000197064 SCV002581484 likely pathogenic Familial cancer of breast 2022-05-18 criteria provided, single submitter clinical testing
King Laboratory,University of Washington RCV001171463 SCV001251374 pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2 2019-09-01 no assertion criteria provided research
CZECANCA consortium RCV001391210 SCV001593126 pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided case-control

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