rs587782008

Variant names:

• chr22-28725083-ATCT-A
• rs587782008
• NM_007194.4:c.483_485delAGA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM4_Supporting PP5 BS2_Supporting

The NM_007194.4(CHEK2):​c.483_485delAGA​(p.Glu161del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000372 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E161E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: CHEK2 NM_007194.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17 U:5
• Conservation: PhyloP100: 5.73
• Publications: 9 publications found

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]

CHEK2 Gene-Disease associations (from GenCC):

• CHEK2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 69 uncertain in NM_007194.4
• PM4: Nonframeshift variant in NON repetitive region in NM_007194.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 22-28725083-ATCT-A is Pathogenic according to our data. Variant chr22-28725083-ATCT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141783.
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.483_485delAGA	p.Glu161del	disruptive_inframe_deletion	Exon 4 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.483_485delAGA	p.Glu161del	disruptive_inframe_deletion	Exon 4 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251418 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461816 Hom.: 0 AF XY: 0.0000316 AC XY: 23 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111962

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:6 Uncertain:3

Jan 17, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PS4_MOD,PM1_SUP,PM2_SUP,PM4_SUP -

Aug 23, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 19, 2022

Institute of Human Genetics, Heidelberg University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2020

Division of Medical Genetics, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in individuals and families with breast cancer (Caminsky 2016, Desrichard 2011, Shirts 2016, Sodha 2002), and functional studies have demonstrated that this variant decreases protein expression and reduces activation and kinase activity (Desrichard 2011, Sodha 2006). This variant has been observed 5 times in the gnomAD database and has an overall allele frequency of 0.00001768 (https://gnomad.broadinstitute.org/). In addition, multiple in silico tools predict a damaging effect on protein structure and function. Based on this information, we consider this variant to be likely pathogenic. PS4-moderate; PP3 -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.483_485del, results in the deletion of 1 amino acid(s) of the CHEK2 protein (p.Glu161del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782008, gnomAD 0.004%). This variant has been observed in individual(s) with breast and/or ovarian cancer and breast cancer and prostate cancer (PMID: 12442270, 26845104, 26898890, 29520813, 30633282, 31341520; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as 481_483del. Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CHEK2 function (PMID: 16982735, 22114986). Studies have shown that this variant is associated with inconclusive levels of altered splicing (internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 09, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16982735]. This variant is expected to disrupt protein structure [Myriad internal data]. -

May 20, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3 Uncertain:1

Aug 11, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect: absent kinase activity, reduced protein expression and stability, and reduced activation in response to DNA damage (PMID: 16982735, 22114986, 36468172); Observed in several individuals with personal and family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (PMID: 12442270, 22114986, 26898890, 26845104, 30633282, 34326862, 34299313); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26845104, 26898890, 31398194, 16982735, 22114986, 12442270, 26681312, 19338683, 27498913, 27621404, 28135136, 28301460, 29922827, 23242139, 12454775, 30633282, 29520813, 30322717, 32805687, 32923877, 36139606, 35441217, 19782031, 22419737, 36468172, 34299313, Natalia[article]2023, 31341520, 34326862, Gebbia2024[PrePrint]) -

Apr 21, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Aug 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 amino acid from the FHA domain of the CHEK2 protein. Functional studies have shown that this variant reduces CHEK2 stability, DNA damage-induced phosphorylation, and kinase activity in vitro (PMID: 16982735, 22114986, 36468172). The reduction in activity was comparable to known pathogenic CHEK2 variants used in the studies. This variant has been observed in individuals affected with breast cancer, with breast cancer reported in first-degree relatives (PMID: 26845104, 30633282; communications with external laboratories: ClinVar SCV000255306, SCV000185293). It has been shown that this variant segregates with disease in multiple families (communication with external laboratory: ClinVar SCV000255306) although segregation was inconclusive in another report (PMID: 26898890). This variant has also been reported in individuals affected with breast and/or ovarian cancer (PMID: 12442270, 26681312, 32923877, 34299313), prostate cancer (PMID: 29520813) and pancreatic cancer (PMID: 29922827). This variant has been identified in 5/282820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Dec 23, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 11, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.483_485delAGA variant (also known as p.E161del) is located in coding exon 3 of the CHEK2 gene. This variant results from an in-frame AGA deletion at nucleotide positions 483 to 485. This results in the in-frame deletion of a glutamic acid at codon 161. This variant is located in the FHA functional domain and has been associated with decreased protein expression, stability, and phosphorylation compared to wild type CHK2 (Sodha N et al. Cancer Res. 2006 Sep;66:8966-70; Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119). Of note, this alteration is also designated as delE161 in published literature. Based on internal structural assessment, this alteration results in disruption of the FHA domain (Cai Z et al. Mol. Cell. 2009 Sep;35:818-29; Ambry internal data). Additionally, this alteration has been identified in cohorts of individuals diagnosed with breast, ovarian, and prostate cancers (Susswein LR et al. Genet. Med. 2016 08;18:823-32; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Wu Y et al. Prostate. 2018 06;78:607-615; Carter NJ et al. Gynecol. Oncol. 2018 12;151:481-488; Hines SL et al. Mol Omics. 2019 02;15:59-66; Guglielmi C et al. Int J Mol Sci, 2021 Jul;22:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Dec 22, 2015

Dr. Peter K. Rogan Lab, Western University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Sequenced patient with familial breast cancer -

Nov 11, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: PS3 (strong pathogenic): Sodha (2006, PMID: 6982735): reduced phosphorylation after DNA damage Desrichard (2011, PMID: 22114986): no kinase activity Wagener (2023, PMID: 36468172): low expression & only slight induction of CHK2-Thr68 phosphorylation upon irradiation + structural modeling from Hines (2019, PMID: 30633282) & Cai (2009, PMID: 19782031) indicate deleterious function, PM4 (medium pathogenic): in-frame in non-repeat region -

Dec 05, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHEK2 c.483_485delAGA (p.Glu161del), also known as 481_483del, results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. Internal evidence suggests that this variant is associated with inconclusive levels of altered splicing (Labcorp, formerly Invitae). The variant allele was found at a frequency of 1.6e-05 in 253044 control chromosomes. c.483_485delAGA has been reported in the presumed heterozygous state in the literature in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (e.g. Sodha_2002, Caminsky_2016, Susswein_2016, Carter_2018, Arvai_2019, Hines_2019, Greville-Heygate_2020). Further, this variant segregated with breast cancer in multiple families (Labcorp, formerly Invitae). The variant has also been reported in individuals with prostate cancer (Wu_2018) and pancreatic cancer (Hu_2018). At least two publications cite experimental evidence evaluating an impact on protein function, reporting that the variant reduces CHEK2 stability and DNA damage-induced phosphorylation and significantly diminishes kinase activity in vitro (Sodha_2006, Desrichard_2011). The following publications have been ascertained in the context of this evaluation (PMID: 31341520, 31398194, 27621404, 26898890, 30322717, 22114986, 32923877, 28301460, 30633282, 29922827, 23242139, 19338683, 26845104, 15488637, 16982735, 12442270, 26681312, 29520813). ClinVar contains an entry for this variant (Variation ID: 141783). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

CHEK2-related cancer predisposition Pathogenic:1

Dec 08, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and colorectal cancer, susceptibility to Pathogenic:1

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CHEK2-related disorder Uncertain:1

Mar 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 c.483_485delAGA variant is predicted to result in an in-frame deletion (p.Glu161del). This variant has been reported in patients with a history of breast or ovarian cancer/tumor (Sodha et al. 2002, PubMed ID: 12442270; Table S1, Susswein et al. 2016, PubMed ID: 26681312; Table S1, Carter et al. 2018. PubMed ID: 30322717). However in one family study, this variant did not segregate with disease in at least two individuals with osteosarcoma and breast cancer (Sodha et al. 2002, PubMed ID: 12442270). In addition, this variant was observed 18 times in a cohort of samples tested for multi-gene hereditary cancer, however no further phenotypic information related to this variant was provided (Table S1, Sutcliffe et al. 2020. PubMed ID: 32805687). Functional studies have revealed that the in-frame p.Glu161del variant impacts CHEK2 protein stability and phosphorylation activity (Sodha et al. 2006, PubMed ID: 16982735). This variant was reported in two individuals with prostate cancer, however, it does not contribute to increased risk of lethal prostate cancer (Table 2, Wu. 2018. PubMed ID: 29520813). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as uncertain or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141783/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587782008; hg19: chr22-29121071;