rs587780181

chr22-28734461-CTCCTCAGGTTCTTGG-Cchr22-28734461-CTCCTCAGGTTCTTGG-CTCCTCAGGTTCTTGGTCCTCAGGTTCTTGG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4 BP6

The NM_007194.4(CHEK2):c.246_260del(p.Asp82_Glu86del) variant causes a 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 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18 B:3
• 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]

ACMG classification

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=17, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.246_260del	p.Asp82_Glu86del	inframe_deletion	2/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.246_260del	p.Asp82_Glu86del	inframe_deletion	2/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152066 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251436 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135898

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000131 AC: 192 AN: 1461882 Hom.: 0 AF XY: 0.000117 AC XY: 85 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152066 Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6 AN XY: 74276

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:18 Benign:3

Revision: criteria provided, conflicting classifications

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	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	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	Invitae	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:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 22, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
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	- -

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	Revvity Omics, Revvity	Oct 11, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 19, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	In-frame deletion of 5 amino acids in a non-repeat region; Observed in individuals with CHEK2-related cancers and other cancers (Dong et al., 2003; Bell et al., 2007; Yurgelun et al., 2015; Scarpa et al., 2017; Hauke et al., 2018; Tian et al., 2019; Gao et al., 2021; Abdel-Razeq et al., 2022); Published functional studies are inconclusive: reduced, but not absent, protein expression and kinase activity (Bell et al., 2007; Scarpa et al., 2017); In silico analysis supports 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) -

not specified Uncertain:3 Benign:1

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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
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	- -

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

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587780181; hg19: chr22-29130449;