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

dbSNP: rs764884641

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197064	SCV000254953	pathogenic	Familial cancer of breast	2024-01-31	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 (PMID: 22114986, 32906215; Invitae). 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	2023-07-03	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. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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	2024-09-13	criteria provided, single submitter	clinical testing	RNA studies demonstrate a damaging effect: aberrant splicing leading to both in-frame and out-of-frame transcripts (PMID: 31050813, 37725924); 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 (PMID: 22114986, 31050813, 30264118, 37453313); Published functional studies demonstrate absent kinase activity (PMID: 31050813); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31843900, 22114986, 27485037, 32906215, 25186627, 31422574, 33050356, 32091409, 35155181, 31050813, 30264118, 37725924, 34326862, 37453313, 36260514, 38554551, 38332730, Privat2024[article], 33047316, 35534704, 36495689)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656831	SCV000888125	likely pathogenic	not provided	2023-06-16	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35155181 (2021), 33050356 (2020), 31050813 (2019), 30264118 (2018), 22114986 (2011)). Functional studies demonstrate abnormal splicing and loss of CHEK2 protein kinase function (PMID: 31843900 (2019), 31050813 (2019), 30264118 (2018)). The frequency of this variant in the general population, 0.000099 (5/50340 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper CHEK2 mRNA splicing . Based on the available information, this variant is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000222175	SCV000910787	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides at the +4 to +7 position of intron 7 of the CHEK2 gene. 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 is 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	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.846+4_846+7delAGTA alters a conserved nucleotide 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 a 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. The following publications have been ascertained in the context of this evaluation (PMID: 25186627, 22114986, 31422574, 31050813, 32906215, 31843900, 33050356, 35155181). ClinVar contains an entry for this variant (Variation ID: 216652). Based on the evidence outlined above, the variant was classified as 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
CeGaT Center for Human Genetics Tuebingen	RCV000656831	SCV002821116	likely pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	CHEK2: PM2, PS3:Moderate, PP1, PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656831	SCV003800241	likely pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing	The CHEK2 c.846+4_846+7del variant (rs764884641) is reported in the literature in individuals and families affected with breast cancer (Desrichard 2011, Kleiblova 2019, Mersch 2018). Some individuals carrying this variant are unaffected, suggesting reduced penetrance, and others also carry pathogenic variants in other cancer-associated genes (Kleiblova 2019). This variant is reported in ClinVar (Variation ID: 216652), and is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes four nucleotides in intron 7, and computational analyses (Alamut v.1.5.1) predict that this variant may impact splicing by significantly weakening the nearby canonical donor splice site. Functional analyses demonstrate skipping of exon 7 or both exons 7 and 8, and also a significant decrease in kinase activity (Casadei 2019, Kleiblova 2019). Based on available information, this variant is considered to be likely pathogenic. References: Casadei S et al. Characterization of splice-altering mutations in inherited predisposition to cancer. Proc Natl Acad Sci U S A. 2019 Dec 16;116(52):26798–807. PMID: 31843900. Desrichard A et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. PMID: 22114986. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Mersch J et al. Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing. JAMA. 2018 Sep 25;320(12):1266-1274. PMID: 30264118.
Myriad Genetics, Inc.	RCV000197064	SCV004044125	pathogenic	Familial cancer of breast	2023-06-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad Internal Data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000197064	SCV004217653	likely pathogenic	Familial cancer of breast	2024-03-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000197064	SCV004698110	likely pathogenic	Familial cancer of breast	2024-02-26	criteria provided, single submitter	clinical testing	Criteria applied: PS3_MOD,PS4_MOD,PM2_SUP,PP3
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV004554748	SCV005044020	likely pathogenic	Li-Fraumeni syndrome 2	2024-01-25	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV002229123	SCV005045694	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-10	criteria provided, single submitter	clinical testing	The c.846+4_846+7del variant in intron 7 of the CHEK2 gene has been reported in more than 10 individuals affected with breast cancer (PMID: 22114986, 30264118, 31050813). It was shown to produce two mutant transcripts in an RNA study (PMID: 31050813). One mutant transcript results in out-of-frame skipping of exons 7 and 8, creating a frameshift and a premature translation stop signal expected to result in an absent or non-functional protein product. The other mutant transcript results in an in-frame skipping of exon 7, creating a partial deletion of the kinase domain and significantly decreased kinase activity (PMID: 31050813). This variant has been identified in 8/278088 alleles in the gnomAD population database. Therefore, the c.846+4_846+7del variant in the CHEK2 gene is classified as Likely Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000656831	SCV005089762	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV004668848	SCV005093841	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-07-17	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PS4, PP1, PP3, PP5; Variant was found in heterozygous state.
Genetic Services Laboratory, University of Chicago	RCV000343110	SCV000594117	uncertain significance	not specified	2016-08-12	flagged submission	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
BRCAlab, Lund University	RCV000197064	SCV002588969	likely pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128154	SCV003804359	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing