rs587780181
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4BP6
The NM_007194.4(CHEK2):c.246_260delCCAAGAACCTGAGGA(p.Asp82_Glu86del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 disruptive_inframe_deletion
NM_007194.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.336
Genes affected
CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_007194.4.
BP6
Variant 22-28734461-CTCCTCAGGTTCTTGG-C is Benign according to our data. Variant chr22-28734461-CTCCTCAGGTTCTTGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128069.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=18, Likely_benign=2}.
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes 0.000105 AC: 16AN: 152066Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000147 AC: 37AN: 251436Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135898
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GnomAD4 exome AF: 0.000131 AC: 192AN: 1461882Hom.: 0 AF XY: 0.000117 AC XY: 85AN XY: 727242
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GnomAD4 genome 0.000105 AC: 16AN: 152066Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6AN XY: 74276
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:20Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 04, 2023 | _x000D_ Criteria applied: PS3_MOD, PM4, PS4_SUP - |
| Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 04, 2023 | This variant, c.246_260del, results in the deletion of 5 amino acid(s) of the CHEK2 protein (p.Asp82_Glu86del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587780181, gnomAD 0.03%). This variant has been observed in individual(s) with breast cancer, prostate cancer, non-Hodgkin's lymphoma, as well as in an individual who underwent genetic testing for Lynch syndrome (PMID: 11949635, 12533788, 17721994, 25980754, 28199314). This variant is also known as 245del15, del223-237, delP75-E79 and D77–E82del. ClinVar contains an entry for this variant (Variation ID: 128069). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CHEK2 function (PMID: 17721994, 28199314). Another study showed significant reduction of kinase activity, however, when normalized to protein expression level, kinase activity was similar to wild-type (Scarpa 2017) 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 10, 2022 | ACMG classification criteria: PS3 supporting, PM4 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This variant, c.246_260del, results in the deletion of 5 amino acid(s) of the CHEK2 protein (p.Asp82_Glu86del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587780181, gnomAD 0.03%). This variant has been observed in individual(s) with breast cancer, prostate cancer, non-Hodgkin's lymphoma, as well as in an individual who underwent genetic testing for Lynch syndrome (PMID: 11949635, 12533788, 17721994, 25980754, 28199314). This variant is also known as 245del15, del223-237, delP75-E79 and D77–E82del. ClinVar contains an entry for this variant (Variation ID: 128069). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CHEK2 function (PMID: 17721994, 28199314). 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 26, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 22, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 16, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 22, 2021 | - - |
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | CHEK2: PM4, PS3:Supporting - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2025 | In-frame deletion of 5 amino acids in a non-repeat region; Observed in individuals with personal and/or family history of CHEK2-related and other cancers (PMID: 12533788, 17721994, 25980754, 28199314, 29522266, 31054147, 34630562, 34326862, 35402282, 37316882, 38350919); Published functional studies are inconclusive: reduced, but not absent, protein expression and kinase activity (PMID: 17721994, 28199314); In silico analysis indicates that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 245del15, delP75-E79, and D77_E82del; This variant is associated with the following publications: (PMID: 17721994, 25980754, 12533788, 11949635, 28199314, 29522266, 31054147, 31159747, 32190957, 31843900, 32906215, 35402282, 36479692, 30287823, 34630562, 36243179, 34326862, 37316882, 38350919) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 11, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 02, 2024 | The CHEK2 c.246_260del (p.Asp82_Glu86del) variant (also known as 245del15, del223-237, delP75-E79, D77-E82del) has been reported in the published literature in individuals with breast/ovarian cancer (PMIDs: 38003901 (2023), 37316882 (2023), 34326862 (2021), 29522266 (2018)), paraganglioma/pheochromocytoma (PMID: 34630562 (2021)), prostate cancer (PMIDs: 32190957 (2020), 12533788 (2003)), Lynch syndrome-associated cancer/polyps (PMID: 25980754 (2015)), and unspecified hereditary cancer (32906215 (2020)). This variant has also been observed in reportedly healthy individuals (PMIDs: 36243179 (2022), 30287823 (2018)). Additionally, this variant co-occurred with a pathogenic variant in the CHEK2 gene in an individual affected with breast cancer in our internal patient population, suggesting this variant may not the primary cause of disease. Functional studies indicate this variant has partial to neutral effects on CHEK2 kinase activity (PMIDs: 28199314 (2017), 17721994 (2007)). The frequency of this variant in the general population, 0.00029 (9/30612 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:3Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2023 | Variant summary: CHEK2 c.246_260del15 (p.Asp82_Glu86del) results in an in-frame deletion that is predicted to remove 5 amino acids from the encoded protein. The variant allele was found at a frequency of 0.00013 in 299744 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Breast Cancer (0.00013 vs 0.00031), allowing no conclusion about variant significance. c.246_260del15 has been reported in the literature in two sporadic prostate cancer patients, one Non-Hodgkin's lymphoma patient, one patient being tested for Lynch syndrome, a patient with primary pancreatic neuroendocrine tumors and in settings of multigene panel testing for breast/ovarian cancer, however without a strong evidence for causality (example, Dong_2003, Bell_2007, Hangaishi_2002, Yurgelun_2015, Scarpa_2017, Tsaousis_2019, Vargas-Parra_2020). The patient with Non-Hodkin's lymphoma also carried a cytogenetic abnormality, t(11;14)(q13;q32) translocation, with rearrangement between the cyclin D1 gene and the JH region of immunoglobulin heavy chain causing overexpression of cyclin D (Hangaishi_2002). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer and/or CHEK2-associated phenotypes. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in attenuated phosphorylation activity (40-50% of WT level) (Bell_2007), while an independent functional study showed the variant to reduce expression, but retain normal kinase activity once protein expression has been accounted for (Scarpa_2017). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=15) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 22, 2021 | DNA sequence analysis of the CHEK2 gene demonstrated a 15 base pair deletion in exon 2, c.246_260del. This in-frame deletion is predicted to result in the deletion of a 5 amino acid residues, p.Asp82_Glu86del. This in-frame deletion has been described in gnomAD with a frequency of approximately 0.03% in the South Asian sub-population (dbSNP rs587780181). This deletion is not located in a known functional domain. This sequence change was observed in two individuals with prostate cancer, in one individual with a history of Lynch syndrome-associated cancer, and in one individual with a pancreatic neuroendocrine tumor (PMID: 28199314, 12533788, 17721994, 11949635, 25980754). Functional studies showed retention of 40-50% of wild-type kinase activity, suggesting partial loss-of-function (PMID:17721994). Another study showed significant reduction of kinase activity, however, when normalized to protein expression level, kinase activity was similar to wild-type (PMID:28199314). Due to the lack of sufficient evidences, the clinical and functional significance of this sequence change is not known at present. - |
| Benign, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
CHEK2-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 08, 2024 | The CHEK2 c.246_260del15 variant is predicted to result in an in-frame deletion (p.Asp82_Glu86del). This variant (reported as 245del15) was identified in an individual with sporadic prostate cancer (Table 1, Dong et al. 2003. PubMed ID: 12533788). This variant (reported as delP75-E79) was also identified in individuals with early onset breast and prostate cancer, but in vitro analysis revealed this variant exhibited only partial loss of protein function with 40-50% of normal activity (Bell et al 2007. PubMed ID: 17721994). Functional studies suggest that this variant (referred to as D77-E82del) showed low kinase activity as a result of reduced protein expression (Scarpa et al. 2017. PubMed ID: 28199314). It was also identified in a patient with suspected Lynch syndrome and was classified as a variant of uncertain significance (Table S2, Yurgelun et al. 2017. PubMed ID: 25980754). This variant is reported in 0.029% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain significance by the vast majority of clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128069/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 27, 2021 | - - |
Predisposition to cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jun 24, 2021 | The CHEK2 c.246_260del (p.Asp82_Glu86del) change has a maximum subpopulation frequency of 0.029% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/22-29130449-CTCCTCAGGTTCTTGG-C?dataset=gnomad_r2_1). The change results in the deletion of five amino acid residues in the CHEK2 protein (PM4). In a functional assay of CHEK2 kinase activity, the mutant protein exhibited 40-50% activity as compared to the wild-type (PS3_Supporting; PMID: 17721994). This variant has been reported in individuals with breast cancer, endometrial cancer, and suspected Lynch syndrome (PMID: 31054147, 25980754, 29522266). It is present 1x in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/). This alteration is also designated 245del15 and delP75_E79 in published literature. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PS3_Supporting, PM4. - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Asp82_Glu86del variant was identified in 4 of 3682 proband chromosomes (frequency: 0.001) from individuals or families with Lynch syndrome-associated cancer and/or polyps, early onset prostate cancer, sporadic prostate cancer, and pancreatic neuroendocrine tumor and was not identified in 846 control chromosomes from healthy individuals (Yurgelun 2015, Scarpa 2017, Bell 2007, Dong 2003). The variant was also identified in dbSNP (ID: rs587780181) as “With Uncertain significance allele”, ClinVar (7x as uncertain significance by GeneDx, Ambry, Invitae, Counsyl, Quest and Integrated Genetics). The variant was identified in control databases in 40 of 277142 chromosomes at a frequency of 0.00014 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 9 of 30780 chromosomes (freq: 0.0003), European (Finnish) in 7 of 25788 chromosomes (freq: 0.0003), East Asian in 4 of 18862 chromosomes (freq: 0.0002), Ashkenazi Jewish* in 2 of 10152 chromosomes (freq: 0.0002), Other in 1 of 6460 chromosomes (freq: 0.00015), Latino in 4 of 34420 chromosomes (freq: 0.0001), European (Non-Finnish) in 12 of 126666 chromosomes (freq: 0.000095), and African in 1 of 24014 chromosomes (freq: 0.00004). This variant is an in-frame deletion resulting in the removal of 5 amino acid residues beginning at the aspartic acid (asp) residue at codon 82 to (glu) residue at codon 86; the impact of this alteration on CHEK2 protein function is not known. In vitro analysis of CHEK2 c.246_260del15 showed retention of 40-50% of wild-type kinase activity, suggesting partial loss-of-function (Bell 2007). Another study showed significant reduction of kinase activity, however, when normalized to protein expression level, kinase activity was similar to wild-type (Scarpa 2017). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 08, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at