Submissions for variant NM_007194.4(CHEK2):c.231CCAAGAACCTGAGGA[1] (p.77DQEPE[1])

dbSNP: rs587780181

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587933	SCV000149919	uncertain significance	not provided	2024-02-26	criteria provided, single submitter	clinical testing	In-frame deletion of 5 amino acids in a non-repeat region; Observed in individuals with CHEK2-related cancers and other cancers (PMID: 12533788, 17721994, 25980754, 28199314, 29522266, 31054147, 34630562, 35402282); Published functional studies are inconclusive: reduced, but not absent, protein expression and kinase activity (PMID: 17721994, 28199314); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; 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)
Ambry Genetics	RCV000116010	SCV000185083	likely benign	Hereditary cancer-predisposing syndrome	2024-02-05	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197398	SCV000254936	uncertain significance	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000197398	SCV000488956	uncertain significance	Familial cancer of breast	2016-07-26	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000116010	SCV000821998	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587933	SCV000889328	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00029 (9/30612 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 29522266 (2018)), Lynch syndrome (PMID: 25980754 (2015)), and prostate cancer (PMID: 32190957 (2020), 12533788 (2003)). The variant has also been reported in an unaffected individual (PMID: 30287823 (2018)). Functional studies in the published literature report that this variant causes reduced kinase activity of the CHEK2 protein (PMID: 17721994 (2007)). Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000116010	SCV000902674	likely benign	Hereditary cancer-predisposing syndrome	2015-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212408	SCV000916883	uncertain significance	not specified	2023-11-10	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000587933	SCV001153651	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CHEK2: PM4, PS3:Supporting
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001543105	SCV001761611	uncertain significance	Predisposition to cancer	2021-06-24	criteria provided, single submitter	clinical testing	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.
Genetic Services Laboratory, University of Chicago	RCV000212408	SCV002065841	uncertain significance	not specified	2021-06-22	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000116010	SCV002537412	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000197398	SCV003807566	uncertain significance	Familial cancer of breast	2022-12-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM4
Revvity Omics, Revvity	RCV000587933	SCV003832009	uncertain significance	not provided	2022-10-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149810	SCV003838796	uncertain significance	Breast and/or ovarian cancer	2021-08-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000197398	SCV003925630	uncertain significance	Familial cancer of breast	2023-04-04	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3_MOD, PM4, PS4_SUP
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000197398	SCV003936124	uncertain significance	Familial cancer of breast	2023-07-04	criteria provided, single submitter	clinical testing	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116010	SCV004014989	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212408	SCV004242542	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV000212408	SCV001251334	benign	not specified	2019-09-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357842	SCV001553431	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV004724810	SCV005339823	uncertain significance	CHEK2-related disorder	2024-03-08	no assertion criteria provided	clinical testing	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.